DEPT OF PHARMACOLOGY
| Researcher : Chan CKY |
| List of Research Outputs |
| Chan C.K.Y., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., Nitric Oxide Synthase and Soluble Guanylyl Cyclase Activation are Required for Hypoxic Endothelium-Dependent Contractions of the Porcine Coronary Artery, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(957.2). |
| Researcher : Cho CH |
| Project Title: | Advances in GI Pharmacology - From Acid Secretion to Mucosal Protection Symposium Non-ulcerogenic Dose of Dexamethasone Delays Gastric Ulcer Healing in Rats |
| Investigator(s): | Cho CH |
| Department: | Pharmacology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 11/2004 |
| Abstract: |
| N/A |
| Project Title: | Adrenaline and its receptor activation on colon cancer growth |
| Investigator(s): | Cho CH |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 02/2006 |
| Abstract: |
| B-Adrenoceptor, a G-protein coupled receoptr, has recently been implicated in the carcinogenesis of different kinds of cancers. It has been reported that actiavtion of B-adrenoceptors could stimulate pulmonary, pancreatic and colon carcinoma cell growth ( Carcinogenesis 1898, 10:1753; Carcinogenesis 2001, 22: 473; Cancer Res. 2005, 65: 5272). Polymorphisms in B-adrenoceptor genes are also associated with increased risk of breast, colon and endometrial cancers (Cancer Res. 2001, 3:264; Int. J. Clin. Oncol 2001, 6:117; Obstet. Gynecol 2003, 102: 506; J.Exp. Clin. Cacner Res. 2004, 23: 669). In addition, B-blockers could inhibit the migration of colon cancer cells induced by noradrenaline (Cancer Res. 2001, 61: 2866). Recent clincial studies also reveal that using B-blockers is negatively associated cancer risk (Rev. Epidemiol. Sante Publiqu 2004, 52: 53; Lancet 1997, 349: 525; Am. J. Hypertens. 1996, 9: 695). All thes findings converge to suggest that adrenoceptors especially B-adrenoceptors indeed play a crucial role in the development of cancer. On the other hand, biobehavioral stresses may influence growth and progression of cancer (Clin. Can. Res. 2003, 9:4514). It has also been demonstrated that altered hormonal and neuronal secretion during stress have a strong impact on the biological activities of breast cancer (Breast Can. Res. Treat. 2003, 80: 63). Among the various stress hormones, adreanline and noradrenaline play an important role in mediating the effect of stress on target cells via adrenergic receptors (Caner 2003, 98: 1547). Indeed our recent study demostrates that cigarette smoke which has been closely associated with cancer development also stimulates colon cancer growth through B-adrenoceptors activation (Cancer Res. 2005, 65:5272). The relationship between stress mediator adrenaline and B-adrenoceptor on colon cancer growth has not been defined. In this study we shall delineate this action and the signal transduction pathway involved will also be investigated. In addition we shall examine the pharmacological action of nicotine, the major active component in cigarette smoke also shown to stimulate adrenaline release in the body, on colon cancer growth. |
| List of Research Outputs |
| Wu W.K.K., Sung J.J., To K.F., Yu L., Li H.T., Li Z.J., Chu K.M., Yu J. and Cho C.H., The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells, Journal of Cell Physiology. 2010, 223: 178-186. |
| Researcher : Chow HM |
| List of Research Outputs |
| Chow H.M., Sun R.W.Y., Lam J.B.B., Li C.K.L., Xu A., Abagyan R., Wang Y. and Che C.M., A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/b-catenin Pathway, Cancer Research. 2010, 70: 329-337. |
| Researcher : Ho YW |
| List of Research Outputs |
| Ho Y.W., Sit S.M., Li R.W.S., Kwan Y.W. and Leung G.P.H., Involvement of Plasma Membrane Monoamine Transporter in Serotonin Uptake in Vascular Smooth Muscle Cells, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 67. |
| Researcher : Huang Q |
| Project Title: | Systematic evaluation and screen of the regions previously linked to osteoporosis in Southern Chinese |
| Investigator(s): | Huang Q, Kung AWC, Sham PC |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 10/2006 |
| Completion Date: | 12/2009 |
| Abstract: |
| To determine whether the genomic regions previously identified in genome scans contribute to osteoporosis/BMD in Southern Chinese by performing genetic linkage analyses; to investigate whether genetic variability in candidate genes in the region of linkage is associated with BMD variation. |
| Project Title: | Large scale association studies of osteoporosis in Chinese |
| Investigator(s): | Huang Q, Kung AWC, Sham PC |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2009 |
| Abstract: |
| (1) Evaluate the association between osteoporosis and 30 most likely candidate osteoporosis susceptibility genes predicted by computational disease gene identification strategy; (2) Identify osteoporosis susceptibility genes on chromosomes 7p that showed good evidence of linkage to osteoporosis in our recent linkage study by peak wide association study. |
| List of Research Outputs |
| Li G.H.Y., Kung A.W.C. and Huang Q., Common variants in FLNB/CRTAP, not ARHGEF3 at 3p are associated with osteoporosis in southern Chinese Women, Osteoporosis International. 2010, 21(6): 1009-20. |
| Researcher : Koo MWL |
| Project Title: | A cell-base co-culture system for the evaluation of green tea catechin, epigallocatechin gallate, in insulin resistance |
| Investigator(s): | Koo MWL |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 01/2009 |
| Abstract: |
| Objectives: Obesity is a health harzard that is usually accompanied by metabolic disturbances such as insulin resistance, hyperglycemia, dyslipidemia, hypertension, and other components of the metabolic syndrome (1). Insulin resistance is highly associated with increased visceral adipose tissue mass which is one of the major risk factors for the development of type 2 diabetes (2). It is now believed that a negative cross-talk between excess body fat and skeletal muscle disturbs insulin signaling in muscle and finally generates muscle insulin resistance (3). Since skeletal muscle accounts for about 80% of total glucose disposal under insulin-stimulated condition therefore defects of insulin action in muscle are central to the pathogenesis of type 2 diabetes (4). However, the mechanism responsible for the reduced sensitivity of muscle to insulin still remains unclear (5). Recent studies demonstrated that adipose tissue is a major secretory and endocrine organ. A variety of factors, i.e., adipokines, released from adipose cells potentially mediate skeletal muscle insulin resistance (6). During the development of obesity and type 2 diabetes these cells increase in size and number and their metabolic activity is dramatically altered. It is conceivable that some of the adipocyte-derived factors could underlie the development of insulin resistance (7). Furthermore, a study by Goodpaster et al. (8) using cross-sectional computed tomography imaging has shown that adipose tissue dispersed within muscle strongly correlated to insulin resistance. Thus, a paracrine interaction of fat and muscle cells may represent a key step in the development of muscle insulin resistance, although the molecular mechanism is not fully understood (9). Antiobesity effects of green tea and its major tea catechin epigallocatechin gallate, EGCG, are widely reported in epidemiological, cell culture, animal, and clinical studies (10,11). A reduction in adipose tissue mass was observed in animals supplemented with EGCG (12). Consumption of EGCG containing capsules also increased fat oxidation and thermogenesis in human subjects (13, 14). Clincal studies on the long-term consumption of green tea or EGCG reduced the incidence of obesity (15) and study done in Japanese showed that 12 weeks administration of tea catechins in a dose of 400-600mg/day reduced body fat (16). A strong positive correlation was also discovered in a cross-sectional survey in a Hong Kong general practice population on tea consumption with a decrease in body mass index and body fat (17). These in vivo and in vitro observations seem to suggest that EGCG may be able to induce changes in adipocyte functions resulting in a decrease in fat tissues in the body. It is thus important to examine if EGCG may improve insulin sensitivity in muscle. In an attempt of studying these interactions under a more physiological condition, a co-culture system of differentiated adipocytes and skeletal muscle cells will be used. The co-culture system allows direct analysis of adipokines secreted from adipocytes on muscle cells rather than at the whole-body level in which interpretation of direct corss-talk between fat and muscle may be confounded by influences such as centrally mediated effects (18). Using this model, it is possible to study if adipocytes disturb insulin signaling in muscle cells and whether this can be prevented by EGCG. References: 1. Bosello O, Zamboni M (2000). Visceral obesity and metabolic syndrome. Obes Rev 1:47-56 2. Bloomgarden ZT (2000). Obesity and diabetes. Diabetes Care 23:1584-1590 3. Groop LC (1999). Insulin resistance: the fundamental trigger of type 2 diabetes. Diabetes Obes Metab 1(Suppl. 1):S1-S7 4. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981). The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30:1000-1007 5. Boden G (1997). Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46:3-10 6. Trayhurn P, Beattie JH (2001). Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329-339 7. Juhan-Vague I, Alessi MC, Morange PE (2000). Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med 32(suppl 1):78-84 8. Goodpaster BH, Thaete FL, Kelley DE (2000). Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 71:885-892 9. Bjorntorp P (1999). Neuroendocrine perturbation as a cause of insulin resistance. Diabetes Metab Res Rev 15:427-441 10. Klaus S, Pultz S, Thone-Reineke C, Wolfram S (2005). Epigallocatechin gallate attenuates diet-induced obesity in mice by decreasing energy absorption and increasing fat oxidation. Int J Obes 29:615-23 11. Zheng G, Sayama K, Okubo T, Juneja LR, Oguni I (2004). Anti-obesity effects of the major components of green tea, catechins, caffeine and theanine in mice. In Vivo 18:55-62 12. Wolfram S, Raederstorff D, Wang Y, Teixeira SR, Elste V, Weber P (2005). Teavigo (epigallocatechin gallate) supplementation prevents obesity in rodents by reducing adipose tissue mass. Ann Nutr Metab 49:54-63 13. Dulloo AG, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P, Vandermander J (1999). Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr 70:1040-1045 14. Dulloo AG, Seydoux J, Girardier L, Chantre P, Vandermander J (2000). Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity. Int J Obes Relat Metab Disord 24:252- 258 15. Nagao T, Komine Y, Soga S, Meguro S, Hase T, Tanaka Y, Tokimitsu I (2005). Ingestion of a tea rich in catechins leads to a reduction in body fat and malondialdehyde-modified LDL in men. Am J Clin Nutr 81:122-129 16. Tsuchida T, Itakura H, Nakamura H (2002). Reduction of body fat in humans by long-term ingestion of catechins. Prog Med 22:2189-203 17. Fong KK (2004). Correlation of obesity with tea consumption in a Hong Kong general practice population: a cross-sectional survey. Master of Medical Sciences thesis, The University of Hong Kong 18. Kusminski CM, McTernan PG, Schraw T, Kos K, O'Hare JP, Ahima R, Kumar S, Scherer PE (2007). Adiponection complexes in human cerebrospinal fulid: distinct complex distribution from serum. Diabetologia 50:634-642 |
| List of Research Outputs |
| Chan K.H., Ho S.P., Yeung S.C., So H.L., Cho C.H., Koo M.W.L., Lam W.K., Ip M.S.M., Man R.Y.K. and Mak J.C.W., Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine. 2009, 103: 1746-1754. |
| Cheung K.W., Sze D.M.Y., Koo M.W.L. and Chan G.C.F., Artepillin C could suppress allogeneic human CD4T cells proliferation as brazilian green propolis but with different mechanisms., 14th Research Postgraduate Symposium, LKS Faculty of Medicine, The University of Hong Kong. (oral presentation) Dec 2-3. 2009. |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., Contractions of the SHR Aorta to High Doses of Epigallocatechin Gallate are Due to Vasoconstrictor Prostanoids, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(960.2). |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., High Concentrations Of Epigallocatechin Gallate Induce Contractions Of The Rat Aorta Due To Production Of Reactive Oxygen Species, Activation Of Cyclooxygenase, Production Of Prostanoids And Stimulation Of TP-Receptors, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 58. |
| Researcher : Lam JKW |
| Project Title: | Investigation of intracellular trafficking of peptide-based nucleic acids delivery system using live cell confocal imaging |
| Investigator(s): | Lam JKW |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 01/2010 |
| Abstract: |
| The use of nucleic acids including both DNA and siRNA as therapeutic agents has huge potential to treat many diseases such as cancers, genetic disorders and infectious diseases [1-4]. Plasmid DNA could be used to induce or enhance the expression of therapeutic protein, whereas siRNA could be used to inhibit the expression of an unwanted protein through RNA interference mechanism. One major obstacle that hinders both types of nucleic acids to be used in the clinic is delivery. Although viruses are efficient nucleic acids delivering vectors by nature, safety concerns such as immunogenicity, risk of insertional mutagenesis and toxicity have led to the development of safer alternatives, non-viral vectors [5]. Commonly used non-viral vectors include cationic polymers, lipids and peptides, but their efficiency is relatively poor. Endosomal escape and nuclear entry (for DNA delivery) present the biggest challenge for non-viral nucleic acid delivery. Evidence suggests that non-viral delivery vectors are capable of entering cells by endocytosis but remain entrapped in endosomes [6]. Subsequently the nucleic acids to be delivered are transported to lysosomes where they are degraded. Therefore the success of endosomal escape is one of the key factors determining the success of nucleic acids delivery. In the case the DNA delivery, therapeutic DNA must also be able enter into the nucleus where the DNA is transcribed into messenger RNA which will be subsequently translated into therapeutic protein in the cytoplasm. Nucleus is well protected by the nuclear envelope which consists of tiny nuclear pores with diameter of an opening of 9 nm (up to 26 nm when dilated); nuclear entry of macromolecules is extremely difficult. Although delivery systems could enter the nucleus during cells division, the process is still inefficient and this will limit the potential of DNA therapy to rapidly dividing cells only. Many non-viral vectors being investigated demonstrated DNA or siRNA transfection, but their efficiency is in order of magnitude lower than viruses and is insufficient for therapeutic application. Our current knowledge of cellular uptake and subsequent intracellular trafficking of non-viral vectors is in fact very limited. Efficiency of non-viral delivery system could be hugely improved by development of appropriate strategy and rational design of the delivery vectors. This requires a good understanding of uptake pathway and intracellular trafficking mechanism of currently developing system. Cellular uptake pathway will determine the fate of a delivery system. For example, uptake through clathrin-mediated endocytosis or macropinocytosis often leads to endosomes entrapment, in which case an efficient endosomal escape mechanism must be sought. On the other hand, caveolae-mediated endocytosis could potentially bypass the unwanted endosomal route. In this project, amphipathic peptides will be used as nucleic acids delivery vector to study their cellular uptake pathway and intracellular transport mechanism. Amphipathic peptide has emerged as a promising candidate for both DNA and siRNA delivery vector. It consists of both hydrophilic and hydrophobic domain. It can bind to the nucleic acids and at the same time provides pH dependent membrane destabilizing activity and promote endosomal escape [7]. In addition, a nuclear localizing signal could be incorporated with the peptide to facilitate nuclear entry for DNA delivery. A series of structurally related amphipathic peptides (LAH4X1F1, LAH4X1F2, LAH6X1 and LAH6X1L) previously demonstrated DNA and/or siRNA transfection in vitro to a different extent. Amongst these peptides, LAH6X1L was the most efficient peptide for both DNA and siRNA transfection. LAH6-X1L has the highest number of lysine (13) and histidine (6) residues. It is hypothesized that the extra lysine residue(s) increase the nucleic acid binding affinity whereas the extra histidine residue(s) promote endosomal escape. The understanding of how the sequence of peptide affects the uptake pathway, the efficiency of endosomal escape and nuclear entry will allow us to design an optimal sequence of nucleic acids delivery in a rational way. In addition, since the physical properties of DNA and siRNA are very different [8], the influence of peptide sequence on the intracellular delivery of these two types of nucleic acid will be compared. Traditional fixed cells imaging was employed in the past to localize non-viral nucleic acids delivery system inside the cell. The problem with this approach is that the number of time points being studied is limited and some of the important events could be be missed. In addition, images at different time points are taken from different cells. A live cell imaging technique using spinning disc confocal microscopy is now available within the faculty. This newly developed exciting technology is the perfect technique to study the intracellular trafficking of our delivery system within the cells. By fluorescently labeling the DNA or siRNA, and different intracellular compartments of the cells (e.g. endosomes, lysosomes, nucleus etc.), we aim to follow the intracellular trafficking of the DNA or siRNA within the cells in an undisrupted manner using live cell confocal imaging technique. The main purposes of this project are: 1) Study the intracellular trafficking mechanism of peptide-based delivery system using live cells confocal imaging, and to evaluate i. efficiency of endosomal or lysosomal escape ii. intracellular movement iii. nuclear entry for each peptide system 2) Compare the differences (if any) between DNA and siRNA delivery for each peptide system [1] C. Huang, M. Li, C.Y. Chen, Q.Z. Yao, Small interfering RNA therapy in cancer: mechanism, potential targets, and clinical applications. Expert Opinion on Therapeutic Targets 12(5) (2008) 637-645. [2] M. Wood, H. Yin, G. McClorey, Modulating the expression of disease genes with RNA-Based therapy. Plos Genetics 3(6) (2007) 845-854. [3] A. El-Aneed, Current strategies in cancer gene therapy. European Journal of Pharmacology 498(1-3) (2004) 1-8. [4] M.L. Edelstein, M.R. Abedi, J. Wixon, R.M. Edelstein, Gene therapy clinical trials worldwide 1989-2004 - an overview. Journal of Gene Medicine 6(6) (2004) 597-602. [5] S.D. Li, L. Huang, Gene therapy progress and prospects: non-viral gene therapy by systemic delivery. Gene Ther. 13(18) (2006) 1313-1319. [6] I.A. Khalil, K. Kogure, H. Akita, H. Harashima, Uptake pathways and subsequent intracellular trafficking in nonviral gene delivery. Pharmacol Rev 58(1) (2006) 32-45. [7] P. Midoux, C. Pichon, J.J. Yaouanc, P.A. Jaffres, Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers. British Journal of Pharmacology 157(2) (2009) 166-178. [8] D.J. Gary, N. Puri, Y.Y. Won, Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery. 4th International Nanomedicine and Drug Delivery Symposium, Omaha, NE, 2006, pp. 64-73. |
| Project Title: | 3rd International Symposium (CDTM 2010 Symposium) Endocytic DNA and siRNA delivery mediated by pH sensitive peptides |
| Investigator(s): | Lam JKW |
| Department: | Pharmacology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 06/2010 |
| Completion Date: | 06/2010 |
| Abstract: |
| N/A |
| List of Research Outputs |
| Davies J.T., Lam J.K.W., Tomlins P.E. and Marshall D., An in vitro multi-parametric approach to measuring the effect of implant surface characteristics on cell behaviour, Biomedical Materials. 2010, 5: 15002. |
| Lam J.K.W., Current Challenges in Nucleic Acids Delivery, Surgical Research Workshop, LSK Faculty of Medicine, The University of Hong Kong. 2010. |
| Lam J.K.W., Endocytic DNA and siRNA mediated by pH sensitive peptides, Pharmaceutical Science Division, King's College London, UK. 2010. |
| Lam J.K.W., Armes S.P., Lewis A.L. and Stolnik S., Folate conjugated phosphorylcholine-based polycations for specific targeting in nucleic acids delivery, Journal of Drug Targeting. 2009, 17: 512. |
| Lam J.K.W., Armes S.P. and Stolnik S., The involvement of microtubules and actin filaments in the intracellular transport of non-viral gene delivery system, Journal of Drug Targeting. 2010. |
| Lam J.K.W., pH responsive peptides for nucleic acids delivery, School of Pharmacy, The Chinese University of Hong Kong. 2010. |
| So M.S.W., Witt K., Lan Y., Mason A.J. and Lam J.K.W., Endocytic DNA and siRNA delivery mediated by pH sensitive peptides, The Third Cellular Delivery of Therapeutic Macromolecules International Symposium. 2010. |
| Researcher : Lau YT |
| List of Research Outputs |
| Lau Y.T., Leung S.W.S. and Man R.Y.K., Potentiation of Kaempferol on Sodium Nitroprusside-induced Relazation in Porcine Coronary Arteries, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.09. |
| Lau Y.T., Leung S.W.S. and Man R.Y.K., The Flavonoid Kaempferol Enhances Sodium Nitroprusside-Induced Relaxation in Porcine Coronary Arteries Via Activation of Potassium Channels, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 69. |
| Researcher : Law KM |
| List of Research Outputs |
| Law K.M., Xu A., Lam K.S.L., Liu T.C., Berger T., Mak T.W., Zhang M.X.M. and Wang Y., Lipocalin 2-deficiency Attenuates Insulin Resistance Induced by High Fat Diet and Aging through Regulation of Lipid Metabolism and Inflammation in Adipose Tissue, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.06. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T., Vanhoutte P.M.G.R., Liu T.C., Sweeney G. and Wang Y., Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity., Diabetes. 2010, 59: 872-82. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T.W., Liu T.C., Sweeney G., Zhou M. and Wang Y., Mice Lacking Lipocalin-2 are Protected from Developing Insulin Resistance Associated with Aging and Obesity, 45th Annual Meeting of The European Association for the Study of Diabetes, September 29-October 2, 2009. Vienna - Austria. Diabetologia 2009. 52 supp:1: S20. |
| Liu T.C., Xu A., Lam K.S.L., Man R.Y.K., Vanhoutte P.M.G.R., Mak T.W., Law K.M., Tse H.F., Liang C. and Wang Y., Endothelial Dysfunctions Induced by Aging and Diet-induced Obesity is Attenuated in Lipocalin-2 Knockout Mice, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.16. |
| Liu T.C., Xu A., Man R.Y.K., Mak T.W., Law K.M., Liang C., Vanhoutte P.M.G.R. and Wang Y., Endothelium-dependent Contractions Induced by Aging and Diet-induced Obesity are Attenuated in Lipocalin-2 Deficient Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(570.3). |
| Researcher : Lee MYK |
| List of Research Outputs |
| Lee M.Y.K., Vanhoutte P.M.G.R. and Xu A., Pharmacological Inhibition Of Adipocyte-Fatty Acid Binding Protein (A-FABP) Improves Endothelial Function In Male Apolipoprotein E-Knockout Mice, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 56. |
| Lee M.Y.K., Wang Y. and Vanhoutte P.M.G.R., Senescence of Cultured Porcine Coronary Arterial Endothelial Cells Is Associated with Accelerated Oxidative Stress and Activation of NFKB, Journal of Vascular Research. 2009, 47: 287-298. |
| Zu Y., Liu L.I.N.G., Lee M.Y.K., Xu C., Liang Y., Man R.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells, Circulation Research. 2010, 106: 1384-1393. |
| Zu Y., Liu L., Xu A., Lam K.S.L., Lee M.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells, 34th FEBS Congress, Czech Republic, July 2009. 2009. |
| Researcher : Leung GPH |
| Project Title: | Cloning and characterization of novel equilibrative nucleoside transporter type 4 (ENT4) |
| Investigator(s): | Leung GPH |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 03/2005 |
| Abstract: |
| Background: The physiological important nucleoside, adenosine, acts through adenosine receptors to exert diverse effects on cellular functions such as inhibition of platelet aggregation, slowing of heart rate and vasodilation. Nucleoside transporters are important in adenosine functions by fine-tuning its concentration in the vicinity of adenosine receptors. There are two classes of nucleoside transporters: Na+-dependent concentrative nucleoside transporters (CNTs) and Na+-independent equilibrative nucleoside transporters (ENTs). So far three equilibrative nucleoside transporters (ENTs) have been cloned and characterized. Both ENT1 and ENT2 are broadly selective, transporting purine and pyrimidine nucleosides. Nevertheless, ENT1 is nitrobenzylmercaptopurine ribonucleoside (NBMPR)-sensitive and has an IC50 of 1nM while ENT2 is relatively NBMPR-insensitive and has an IC50 > 1µM. Unlike ENT1 and ENT2, which are plasma membrane proteins, ENT3 is an intracellular protein. It may be responsible for salvaging nucleosides between the cytoplasm and the lumen of Golgi apparatus. Adenosine transport in endothelial cells is Na+-independent. Interestingly, we found that in physiological levels of adenosine (0.1 to 1µM), high concentrations of NBMPR (> 200µM, a concentration that can completely inhibit both ENT1 and ENT2) only reduce 20% of the adenosine transport. It indicates that another nucleoside transporter, which is characteristically distinct from the ENT1 and ENT2, is present in the endothelial cells. Recently, we have cloned a protein from endothelial cells which has 18% amino acid identity with ENT1. We term it ENT4 and hypothesize that it may be a novel isoform of nucleoside transporter. Objectives: In this grant application, we propose to characterize ENT4. In aim I, we will stably transfect ENT4 into nucleoside transporter-deficient cells. In aim II, we will functionally characterize ENT4. We will determine its affinities to different nucleosides and its sensitivities to different inhibitors such as NBMPR. In aim III, we will study the tissue distribution of ENT4. |
| Project Title: | Nimodipine suppresses chemokine release via inhibition of adenosine uptake in endothelial cells |
| Investigator(s): | Leung GPH, Man RYK, Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2007 |
| Completion Date: | 02/2010 |
| Abstract: |
| To strengthen our preliminary study that nimodipine exerts anti-inflammatory effect through the inhibition of adenosine transport; to investigate the mechanism by which nimodipine inhibits ENT1 and ENT2. |
| Project Title: | Function and regulation of cystic fibrosis transmembrane conductance regulator (CFTR) in endothelail cells |
| Investigator(s): | Leung GPH, Vanhoutte PMGR, Man RYK |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 03/2008 |
| Completion Date: | 08/2009 |
| Abstract: |
| Key issues and problems being addressed: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in a variety of epithelial cells, including cells isolated from airway, sweat gland, kidney, intestine and reproductive tract (Kunzelmann 1999). It has been well-received that CFTR functions as a low-conductance, cyclic nucleotide-regulated chloride channel and plays a key role in NaCl and fluid secretion in epithelium (Kunzelmann 1999). Interstingly, CFTR has been recently found in human umbilical vein, human lung pulmonary artery and mouse aorta endothelial cells (Tousson et al, 1998; Wei et al, 2001). However, the role(s) of CFTR in endothelial cell biology is still not understood. Several possibilities exist according to the characterisitics of CFTR. First, CFTR may regulate intracellular pH because HCO3- is permeable to CFTR (Meyer et al, 2000; Poulsen & Machen, 1996 ). Second, CFTR may be important in the regulation of vascular tone by controlling the endothelial cell membrane potential. Any change of membrane potential could affect the Ca2+ influx that in turn alter the Ca2+-mediated signalling pathways and hence the release of vasoactive mediators, such as nitric oxide and prostacyclins (Busse et al, 1991; Carter and Peasson, 1992; Lantoine et al, 1998). Third, previous studies have demonstrated that ATP release is increased when CFTR is over-expressed or activated. Therefore, CFTR may function as a regulator of ATP transport (Jiang et al, 1998). ATP and its metabolites such as adenosine are potent vasoactive autocrine and paracrine substances. The above speculations about the roles of CFTR in endothelial cells remain to be proved. In addition to the functions, the regulation of CFTR in endothelial cells, particularly in pathological states, is also less understood. Diabetes mellitus is known to be a major risk factor for cardiovascular diseases. Hyperglycaemia per se and the overproduction of reactive oxygen species in diabetes are 2 major causes of the impairment of enothelial cell functions (Callaghan et al, 2005; Nascimento et al, 2006). The mechanism leading to endothelial cell dysfunction is not fully revealed but many studies have suggested that it may be related to the change in expression profile of certain genes, such as nitric oxidase synthase and adhesion molecules (Uemura et al, 2001; Ho et al, 1999). Provided that CFTR contributes to the endothelial cell functions, it will be of interest to investigate if the expression and activity of CFTR in endothelial cells are also influenced by diabetes. Purpose of the posposed project: Two objectives are proposed in this project. First, we will justify the role(s) of CFTR in endothelial cells. We will provide experimental evidence to support the functions of CFTR in the regulation of intracellular pH, cell membrane potential and ATP transport. Second, we will study the effects of hyperglycemia and oxidative stress (the two major consequences of diabetes) on CFTR in endothelail cells. Kunzelmann K (1999) The cystic fibrosis transmembrane conductance regulator and its function in epithelial transport. Rev Physiol Biochem Pharmacol 137:1-70. Tousson A, Van Tine BA, Naren AP, Shaw GM, and Schwiebert LM (1998) Characterization of CFTR expression and chloride channel activity in human endothelia. Am J Physiol 275:C1555-1564. Wei L, Freichel M, Jaspers M, Cuppens H, Cassiman JJ, Droogmans G, Flockerzi V, and Nilius B (2001) Functional interaction between TRP4 and CFTR in mouse aorta endothelial cells. BMC Physiol 1:3. Meyer G, Garavaglia ML, Bazzini C, and Botta G (2000) An anion channel in guinea pig gallbladder epithelial cells is highly permeable to HCO-3. Biochem Biophys Res Commun 276:312-320. Poulsen JH and Machen TE (1996) HCO3-dependent pHi regulation in tracheal epithelial cells. Pflugers Arch 432:546-554. Busse R, Luckhoff A, and Mulsch A (1991) Cellular mechanisms controlling EDRF/NO formation in endothelial cells. Basic Res Cardiol 86:7-16. Carter TD and Pearson JD (1992) Regulation of prostacyclin synthesis in endothelial cells. News Physiol Sci 7:64-69. Lantoine F, Iouzalen L, Devynck MA, Millanvoye-Van Brussel E, and David-Dufilho M 1998 Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2+ influx. Biochem J 330:695-699. Jiang Q, Mak D, Devidas S, Schwiebert EM, Bragin A, Zhang Y, Skach WR, Guggino WB, Foskett JK, and Engelhardt JF (1998) Cystic fibrosis transmembrane conductance regulator-associated ATP release is controlled by a chloride sensor. J Cell Biol 143:645-657. Callaghan MJ, Ceradini DJ, and Gurtner GC (2005) Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function. Antioxid Redox Signal 7:1476-82. Nascimento NR, Lessa LM, Kerntopf MR, Sousa CM, Alves RS, Queiroz MG, Price J, Heimark DB, Larner J, Du X, Brownlee M, Gow A, Davis C, and Fonteles MC (2006) Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide. Proc Natl Acad Sci U S A 103:218-223. Uemura S, Matsushita H, Li W, Glassford AJ, Asagami T, Lee KH, Harrison DG, and Tsao PS (2001) Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. Circ Res 88:1291-1298. Ho FM, Liu SH, Liau CS, Huang PJ, Shiah SG, and Lin-Shiau SY (1999) Nitric oxide prevents apoptosis of human endothelial cells from high glucose exposure during early stage. J Cell Biochem 75:258-263. |
| Project Title: | Characterization and physiological role of 5HT transport systems in vascular cells |
| Investigator(s): | Leung GPH, Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 04/2009 |
| Abstract: |
| Serotonin (5HT) is an important neurotransmitter in the central nervous system and is a local factor controlling the motility and exocrine secretion of gut, but it also affects hemodynamics. In the cardiovascular system, 5HT is mainly stored in platelets, thereby keeping the free circulating 5HT at low levels. 5HT is released during platelets aggregation. The released 5HT feeds back on the platelets to amplify the aggregation process. Moreover, 5HT causes the contraction of vascular smooth muscle cells through the direct stimulation of 5HT2 receptors on the cells (Vanhoutte, 1990). Interestingly, the contractions evoked by 5HT are reduced considerably in the presence of a normal endothelium because the endothelial cells release endothelium-derived relaxing factors (EDRF) when 5HT stimulates 5HT1 receptors on the endothelial cells (Cohen et al., 1983). EDRF inhibits not only vascular smooth muscle contraction but also inhibits platelet aggregation and adhesion to the blood vessel wall (Furlong et al., 1987). In theory, any dysfunction of 5HT on 5HT1 receptors in endothelial cells may weaken the protective role of the endothelium in preventing the overwhelming vasoconstriction and unwanted coagulation of blood. Overstimulation of 5HT2 receptors on vascular smooth muscle cells may exacerbate vasoconstriction and promote smooth muscle mitogenesis. The endothelium-dependent relaxation of platelets is facilitated or unmasked by 5HT2 receptor blockers, as these compounds inhibit the direct activation of vascular smooth muscle caused by 5HT (Van Nueten et al., 1981). 5HT can be taken up by blood vessels. Indeed, the action of 5HT is supposed to be terminated after it is removed from its site of action and is taken up into the cytosol of vascular cells, where 5HT is eventually metabolised by monoamine oxidase-A (Ni et al., 2004). Ni and co-workers concluded that 5HT uptake appeared to be largely independent of the endothelium as removal of this cell layer did not alter 5HT uptake (Ni et al., 2004). However, evidence of 5HT uptake by cultured endothelial cells has been reported (Lee & Fanburg, 1986; Brust et al., 2000). Anyhow, the mechanism of 5HT uptake is crucial to the vascular functions of 5HT because it fine-tunes the availability of 5HT at its cognate receptors. 5HT, as a protonated molecule, is not capable of diffusing across the membrane lipid bilayer. Therefore, it is likely that 5HT is transported into vascular cells by active transport system(s) rather than by simple diffusion. Unlike in central nervous system, fluoxetine cannot completely inhibit the 5HT uptake in both arteries and veins (Ni et al., 2004; Linder et al., 2008), indicating that the serotonin transporter (SERT) is not the only protein taking up 5HT in blood vessels. 5HT uptake in blood vessels may occur through multiple means. Possible candidates responsible for the non-SERT-mediated 5HT uptake in blood vessels include the organic cation transporters (OCTs). The ability of the organic cation transporters (OCT)1 to OCT3 to take up 5HT has been demonstrated in SERT-deficient mice (Chen et al., 2001). However, to our knowledge, OCTs in blood vessels have not been studied. A novel plasma membrane monoamine transporter (PMAT) has been cloned recently (Zhou et al., 2007), which is abundantly expressed in the human brain and avidly transports 5-HT. Although the existence of PMAT in blood vessels has not been reported, our preliminary data from RT-PCR has clearly shown the mRNA of PMAT is expressed in human brain microvascular smooth muscle cells. The question we need to address is the detail mechanisms underlying the 5HT uptake in blood vessels, which have not hitherto been fully identified. In addition, the potential involvement of those 5HT uptake systems in vascular diseases is unknown. Therefore, the present study is designed to: 1) Characterize the 5HT transport systems in endothelial cells and vascular smooth muscle cells. We shall focus on SERT, OCTs and PMAT; and 2) Study the regulation of those 5HT transport systems in hypertension and diabetes mellitus. References: 1) Vanhoutte PM (1990). Cardiovasc Drugs Ther 4 Suppl 1:7-12. 2) Cohen RA, Shepherd JT & Vanhoutte PM (1983), Science 221:273-4. 3) Furlong B, et al. (1987). Br J Pharmacol 90:687-92. 4) Van Nueten JM, et al. (1981). J Pharmacol Exp Ther 218:217-30. 5) Ni W, et al. (2004). J Cardiovasc Pharmacol 43:770-81. 6) Lee SL & Fanburg BL (1986). Am J Physiol 250:C761-5. 7) Brust P, et al. (2000). J Neurochem 74:1241-8. 8) Linder AE, et al. (2008). J Pharmacol Exp Ther 325:714-22. 9) Chen JJ, et al. (2001). Neurosci 21:6348-61. 10) Zhou M, Engel K & Wang J (2007). Biochem Pharmacol 73:147-54. |
| Project Title: | Effects of inflammation on concentrative nucleoside transporter-2 in human brain microvascular endothelial cells |
| Investigator(s): | Leung GPH |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 11/2009 |
| Abstract: |
| Purpose of the proposed investigation: 1) To investigate the effects of inflammatory cytokines on the expression level and activity of CNT-2 in human brain microvascular endothelial cells. 2) To elucidate the signaling pathways involved in the regulation of CNT-2. Key issues and problem addressed: Adenosine is a nucleoside that modulates many physiological responses in cardiovascular system. Extracellular level of adenosine is elevated under adverse conditions such as inflammation (Niemela et al., 2004). Adenosine can activate adenosine A2a receptors on endothelial cells that in turn inhibits IL-6 and IL-8 release and reduces the expression of VCAM-1 and E-selectin (Bouma et al., 1996). Therefore, the increased adenosine level is regarded as an endogenous mechanism of immunosuppression evoked during cellular inflammation (Sands and Palmer, 2005). Given the clinical significance of adenosine-related physiology in cardiovascular system, a better understanding of the regulation of extracellular level of adenosine is necessary. Two mechanisms are known to regulate the extracellular adenosine level: (1) ecto-5’nucleotidase, a membrane-bound enzyme which can metabolize adenosine 5’-monophosphate into adenosine (2) nucleoside transporters, a group of integral membrane proteins that can transport adenosine across the cell membranes. Our previous publication has reported that the expression and activity of ecto-5 nucleotidase are up-regulated in endothelial cells (Li et al, 2008). However, the effect of inflammation on nucleoside transporters has not yet been studied. Endothelial cells contain 3 types of cell membrane-bound nucleoside transporters. Two are equilibrative nucleoside transporters (known as ENT-1, ENT-2) and one is concentrative nucleoside transporter (known as CNT-2). Among those nucleoside transporters, CNT-2 is the predominant one responsible for the uptake of adenosine from extracellular space into endothelial cells. We hypothesize that CNT-2 expression and activity are reduced in inflammation, thereby increasing the availability of adenosine in the vicinity of adenosine receptors. It may serve as a crucial mechanism to prolong and amply the anti-inflammatory effect of adenosine. References: Bouma MG, Van Den Wildenberg FAJM, Buurman WA. Am J Physiol 270: C522-C529;1996. Li R.W., Man R.Y., Vanhoutte P.M., Leung G.P.H. Am J Physiol Heart Cir Physiol 295:H1177-1181;2008. Niemela J, Henttinen T, Yegutkin GG, Airas L, Kujari AM, Rajala P, Jalkanen S. J Immunol 172:1646-53;2004. Sands WA, Palmer TM. Immunol lett 101:1-11;2005. |
| Project Title: | Abacavir, an antiviral nucleoside analogue, increases the risk of cardiovascular events by causing endothelial dysfunction |
| Investigator(s): | Leung GPH, Vanhoutte PMGR, Xia Z |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 11/2009 |
| Abstract: |
| 1) To solidify our preliminary findings suggesting that abacavir deteriorates vascular functions; 2) To study the mechanism(s) underlying abacavir-induced endothelial dysfunction; 3) To characterize the abacavir transport systems in endothelial cells. |
| List of Research Outputs |
| Au A.L.S., Poon C.C.W., Zhang T.Q., Kong S.K., Ho A.H.P., Leung G.P.H. and Kwan Y.W., Distinct Effects of Simvastatin on Cytosolic Ca2+ Changes and Ca2+-Sensing Receptor Expression of Isolated Pancreatic Islets b Cells of Obese/Diabetic Mice, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 68. |
| Ho Y.W., Sit S.M., Li R.W.S., Kwan Y.W. and Leung G.P.H., Involvement of Plasma Membrane Monoamine Transporter in Serotonin Uptake in Vascular Smooth Muscle Cells, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 67. |
| Hoque K.M., Woodward O.M., van Rossum D.B., Zachos N.C., Chen L., Leung G.P.H., Guggino W.B., Guggino S.E. and Tse C.M., Epac1 mediates protein kinase A-independent mechanism of forskolin-activated intestinal chloride secretion, Journal of General Physiology . 2010, 135: 43-58. |
| Leung G.P.H., Interactions of Herbal Medicines with Anticancer Agents, Hong Kong Pharmacy Conference at the Hong Kong Convention and Exhibition Centre. Jan 23-24, 2010. Hong Kong. 2010.. 2010, 32. |
| Li R.W.S., Kwan Y.W. and Leung G.P.H., Effects of abacavir on the vascular and platelet activities., XX World Congress ISHR 2010 Kyoto, Japan. May 13-16, 2010.. 2010, P-2-18-6. |
| Li R.W.S., Kwan Y.W. and Leung G.P.H., Relationship between abacavir and Risk Factors of Cardiovascular Diseases, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 65. |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Binding of Genistein with Membrane Estrogen Receptor and the Potentiating Effect of Genistein in Rapid, Non-Genomic Vascular Action, Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009. Hong Kong. Journal of the Hong Kong College of Cardiology.. 2009, 17(2): 53. |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, Non-genomic Vascular Actions of Genistein Involves a G-protein Coupled Receptor., 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.08. |
| Liu H., Lei S., Luo T., Xia Z.Y., Liu Y., Leung G.P.H., Vanhoutte P.M.G.R., Irwin M.G. and Xia Z., Nitroglycerin Reduces TNF- Toxicity To Endothelial Cells but Compromises the Protective Effects of Propofol, FASEB Journal. 2010, 24: 959.9. |
| Poon C.C.W., Au A.L.S., Zhang T.Q., Kong S.K., Ho A.H.P., Leung G.P.H. and Kwan Y.W., Amelioration of Hyperglycemia-Induced Mitochondrial Ros Generation of Single Pancreatic Islet b-cells of obese/Diabetic Mice by Chronic N-Acetyl-L-Cysteine, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 59. |
| TY L.A.M., SW S.E.T.O., AL A.U., CC P.O.O.N., Li W.S.R., HY L.A.M., WS L.A.U., SW C.H.A.N., SM N.G.A.I., Leung G.P.H., SM L.E.E., SK T.S.U.I. and YW K.W.A.N., Folic acid supplementation modifies beta-adrenoceptor-mediated in vitro lipolysis of obese/diabetic (+db/+db) mice, Experimental biology and medicine (Maywood, N.J.). 2009, 234(9): 1047-1055. |
| Tse L.K., Chan L.H.Y. and Leung G.P.H., Integrating disciplinary content and language to prepare students for PBL in Pharmacy (poster presentation), The 6th International Conference on PBL in dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, December . 2009. |
| Yang C. and Leung G.P.H., 14, 15-epoxyeicosatrienoic Acid Induces Vasorelaxation Throuhg the Prostaglandin EP2 Receptors in Rat Mesenteric Artery, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.23. |
| Zhang T.Q., Wong I.M.F., Au A.L.S., Poon C.C.W., Kong S.K., Ho A.H.P., Leung G.P.H., Cho C.H. and Kwan Y.W., Modulatory Effects of Simvastatin on Insulin Release of Pig Pancreatic Islets of Langerhans, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 69. |
| Researcher : Leung SWS |
| Project Title: | Regulation of endothelial-derived hyperpolarizing factor-mediated responses in physiological and pathological conditions |
| Investigator(s): | Leung SWS, Leung GPH, Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 10/2007 |
| Abstract: |
| To examine the degree of contribution of EDHF-mediated responses to modulate vascular tone at different stages of endothelial dysfunction; to identify the type(s) of EDHF that are involved in vasomotor control at different stages of endothelial dysfunction; to determine whether there is any changes in expression or activity level of protein molecules associated with EDHF-mediated responses at different stages of endothelial dysfunction; to investigate whether change in the production/action of nitric oxide (NO) affects the release of EDHF. |
| Project Title: | Mechanism involved in the induction of endothelial sensecence by atherogenic lipids |
| Investigator(s): | Leung SWS, Man RYK |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 04/2008 |
| Completion Date: | 03/2010 |
| Abstract: |
| Background Atherosclerosis is associated with endothelial dysfunction, manifested as a reduction of nitric oxide release, and expression of inflammatory mediator such as intracellular cell adhesion molecules. These characteristics of atherosclerosis was also observed in cultured endothelial cells that were senescent [1]. Indeed, endothelial senescence was detected in human atherosclerotic lesions [1]. Experimental studies indicated that premature senescence of endothelial cells occurred with intake of high cholesterol diet [2], and in the presence of oxidized low-density lipoprotein [3], both of which are risk factors of atherosclerosis [4]. Oxidation of low-density lipoprotein is associated with a dramatic increase in lysophosphatidylcholine (LPC) [5]. However, the role of LPC in the acceleration of endothelial senescence has not be examined. Both oxidized low-density lipoprotein and LPC are known to stimulate apoptosis in endothelial cells [6-8]. Apoptosis and proliferation of endothelial cells occur naturally as they age, and this repeated turnover (apoptosis and proliferation) develops into endothelial senescence. Experimentally, endothelial senescence is induced by extensive replication in vitro and by mechanical injury through balloon angioplasty in vivo [9-11]. These experimental processes involve apoptosis and/or proliferation of endothelial cells, as demonstrated by a reduction in the expression of vascular endothelial growth factor, and an enhanced activity of ERK 1/2 in those senescent endothelial cells [11,12]. Therefore, it is likely that the progression of senescence is accelerated by the induction of apoptosis by LPC, and that this in turn, stimulates proliferation of endothelial cells. Hypothesis We hypothesize that stimulation of apoptosis by atherogenic phospholipids is responsible for endothelial senescence hence dysfunction that is associated with the development of atherosclerosis. Purpose of the proposed investigation: LPC has been shown to induce endothelial apoptosis through activation of p38/MAPK pathway [8]. However, a potential role of this atherogenic lipid in stimulating senesence of endothelial cells remains to be established. The present proposed study aims at investigating whether or not LPC contributes to endothelial senescence and if so, whether or not the promotion of endothelial apoptosis by LPC is coupled to the progression of endothelial senesence. Key issues and problem addressed: i. The influence of LPC on the senescence of endothelial cells, by examining the morphology and protein expressions that are characteristics of senescent cells in cultured human endothelial cells without or with chronic treatment with LPC e.g. enlarged and flattened morphology and an increased activity of senescence-associated acidic beta-galactosidase [13,14]. ii. Alteration of the expression, phosphorylation and activity of enzymes that are known to involve in cell apoptosis, e.g. p38/MAPK [8], Akt [15] and cyclooxygenase [16], in endothelial cells following exposure to LPC for different time intervals. iii. The potential of inhibiting the induction of apoptosis by LPC using pharmacological approaches to reverse the degree of endothelial senescence following exposure of LPC. Reference: [1] Minamino T, Miyauchi H, Yoshida T, et al. Circulation 2002; 105: 1541-1544. [2] Shi Q, Hubbard GB, Kushwaha RS et al. Am J Physiol Heart Circ Physiol 2007; 292: H2913-H2920. [3] Breitschopf K, Zeiher AM, Dimmeler S. FEBS Lett 2001; 493: 21-25. [4] Parthasarathy S, Steinberg D, Witztum JL. Annu Rev Med 1992; 43: 219-225. [5] Parthasarathy S, Barnett J. Proc Natl Acad Sci USA 1990; 87: 9741-9745. [6] Dimmeler S, Haendeler J, Galle J, et al. Circulation 1997; 95: 1760-1763. [7] Escargueil-Blanc I, Meilhac O, Pieraggi MT, et al. Arterioscler Thromb Vasc Biol 1997; 17: 331-339. [8] Takahashi M, Okazaki H, Ogata Y, et al. Atherosclerosis 2002; 161: 387-394. [9] Foreman KE, Tang J. Exp Gerontol 2003; 38: 1251-1257. [10] Fenton M, Barker S, Kurz DJ, et al. Arterioscler Thromb Vasc Biol 2001; 21: 220-226. [11] Lee MYK, Tse HF, Siu CW, et al. Arterioscler Thromb Vasc Biol 2007; 27: 2443-2449. [12] Jameson M, Dai FX, Luscher T, et al. Hypertension 1993; 21: 280-288. [13] Van der Loo B, Fenton MJ, Erusalimsky JD. Exp Cell Res 1998; 241: 309-315. [14] Dimri GP, Lee X, Basile G, et al. Proc Natl Acad Sci USA 1995; 92: 9363-9367. [15] Kennedy SG, Wagner AJ, Conzen SD, et al. Genes Dev 1997; 17: 338-344. [16] Zou MH, Shi C, Cohen RA. Diabetes 2002; 51: 198-203. |
| Project Title: | Acceleration of the senescence of the endothelium by high blood pressure |
| Investigator(s): | Leung SWS, Lee MYK, Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 11/2008 |
| Abstract: |
| (1) To elucidate the characteristic of endothelial senescence that occurs naturally in vivo, by examining the morphology and protein expressions in the endothelium of the aorta of young and aged SHR with blood pressure normalized by antihypertensive treatments: (2) To correlate the degree of endothelial senescence with the features of endothelial dysfunction, in terms of responses to vasoactive agents, using young and aged SHR rats with blood pressure normalized by antihypertensive treatments as a model; (3) To identify the influence of high blood pressure on the senescence of endothelial cells, by exploring the biochemical changes that may lead to premature replication of endothelial cells in aorta isolated from SHR (i.e. endothelium that is exposed chronically to high blood pressure). Since the severity of hypertension increases as SHR increases in age, these rats at different ages will be used to study whether or not the level of blood pressure is associated with the progression of endothelial senescence; (4) To investigate the role of oxidative stress in the premature replication of endothelial cells leading to acceleration of endothelial senescence observed in spontaneous hypertension. |
| Project Title: | Effect of genistein on the activity of platelets of ovariectomized rats |
| Investigator(s): | Leung SWS, Man RYK |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 05/2009 |
| Abstract: |
| Background Epidemiologial studies suggest that estrogen-replacement therapy in post-menopausal women is associated with an increased risk of cardiovascular thrombotic events [1-3], suggesting that estrogen may be a pro-thrombotic factor. Thrombosis is the result of a pathological activation of the coagulation cascade, which involves the activation of platelets. Upon activation, platelets express P-selectin and glycoprotein (GP) IIb/IIIa receptors for adhesion to vessel wall and for aggregation of platelets [4]. Platelets also release coagulation factors, such as thromboxane A2 (TXA2), adenosine diphosphate (ADP) and tissue factor, and these factors cause further activation and aggregation of platelets resulting in the formation of a more stable thrombus [4]. In view of the important role of platelets in thrombosis, the relationship between estrogen level and platelet function has been extensviely studied [5-8]. Estrogen replacement therapy increased the expressions of P-selectin and GP 53 in the platelets, indicating an increase in platelet activation, in postmenopausal women [5]. An increase in the content of tissue factor in the platelets was also observed in ovariectomized pigs treated with 17beta-estradiol [7], although estrogen supplementation did not affect the release of TXA2 by the platelets [8]. On the other hand, deficiency of 17beta-estradiol due to ovariectomy increased the degree of platelet aggregation, and this increase was reversed in ovariectomized pigs treated with 17beta-estradiol [6,9]. Platelets contain both estrogen receptor alpha and beta (ERalpha and ERbeta, respectively) [10,11]. Therefore, changes in platelets function in reseponse to hormonal status may be due to a direct effect of 17beta-estradiol on the platelets. The presence of estrogen receptors in the platelets also suggest that selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, which are currently used clinically for treatment of osteoporosis and breast cancer, respectively, also affect the activity of the platelets. Indeed, treatment with raloxifene in ovariectomized pigs altered the platelet release of those mediators involved in coagulation cascade, such as TXA2, tissue factors and nitric oxide, but these effects of raloxifene is different to those of 17beta-estradiol [7,8,12]. Similarly, differential modulation of the platelet function was reported following acute exposure of platelets to tamoxifen, its metabolites and 17beta-estradiol [13]. In addition to SERMS, estrogen receptors are also targets for flavonoids [14]. Some of the flavonoids, such as genistein and daidzein, reduce the aggregation of platelets [15-17], although there is controversy over the mechanism of actions through which these flavonoids affect the platelet function. Hypothesis We hypothesize that the flavonoid, genistein, modulates the release of coagulation mediators in the platelets, resulting in reduced platelet aggregation hence thrombotic risk. These effects of genistein may be mediated through estrogen receptors. As the expression of estrogen receptors in the platelets were affected by the hormonal status, with an upregulation of ERalpha and ERbeta following ovariectomy [6], the effects of genistein on the activity of platelets may differ in control and ovariectomized animals. Purpose of the proposed investigation: The present proposed study aims at investigating whether or not genistein provides a protective effect against thrombosis through actions on the platelets, and if so, whether or not these effects of genistein is affected by the hormonal status of the animals. Key issues and problem addressed: i. The influence of genistein on the activity of the platelets, by examining the release of mediators that are involved in the coagulation cascade (e.g. TXA2, tissue factor and nitric oxide), and the expressions of adhesion proteins (e.g. P-selectin and glycoprotein (GP) IIb/IIIa receptors ) [4] following acute exposure to genistein. ii. Modulatory effect of genistein on the activation of platelets by physiological stimuli e.g. thrombin. iii. Effect of genistein on the changes in the platelet function, if any, due to deficiency of female hormones. References: 1. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348: 981-983. 2. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291: 1701-1712. 3. LaCroix AZ. Estrogen with and without progestin: benefits and risks of short-term use. Am J Med 2005; 118: 79S-87S 4. Brass LF, Stalker TJ, Zhu L, Woulfe DS. Signal transduction during platelet plug formation. In: Michaelson AD (ed.). Platelets. Academic Press, Amsterdam, 2007; p.319-346 5. Thijs A, van Baal WM, van der Mooren MJ, Kenemans P, Drager AM, Huijgens PC, Stehouwer CDA. Effects of hormone replacement therapy on blood platelets. Eur J Clin Invest 2002; 32: 613-618. 6. Jayachandran M, Mukherjee R, Steinkamp T, LaBreche P, Bracamonte MP, Okano H, Owen WG, Miller VM. Differential effects of 17β-estradiol, conjugated equine estrogen, and raloxifene on mRNA expression, aggregation, and secretion in platelets. Am J Physiol Heart Circ Physiol 2005; 288: H2355-H2362. 7. Jayachandran M, Sanzo A, Owen WG, Miller VM. Estrogenic regulation of tissue factor and tissue factor pathway inhibitor in platelets. Am J Physiol Heart Circ Physiol 2005; 289: H1908-H1916. 8. Lewis DA, Avsar M, LaBreche P, Bracamonte M, Jayachandran M, Miller VM. Treatement with raloxifene and 17β-estradiol differentially modulates nitric oxide and prostanoids in venous endothelium and platelets of ovariectomized pigs. J Cardiovasc Pharmacol 2006; 48: 231-238. 9. Jayachandran M, Owen WG, Miller VM. Effects of ovariectomy on aggregation, secretion, and metalloproteinases in porcine platelets. Am J Physiol Heart Circ Physiol 2003; 284: H1679-H1685. 10. Khetawat G, Faraday N, Nealen ML, Vijayan KV, Bolton E, Noga SJ, Bray PF. Human megakaryocytes and platelets contain the estrogen receptor β and androgen receptor (AR): testosterone regulates AR expression. Blood 2000; 95: 2289-2296. 11. Jayachandran M, Miller VM. Human platelets contain estrogen receptor , caveolin-1 and estrogen receptor associated proteins. Platelets 2003; 14: 75-81. 12. Abu-Fanne R, Brzezinski A, Golomb M, Grad E, Foldes AJ, Shufaro Y, Varon D, Brill A, Lotan C, Danenberg HD. Effect of estradiol and raloxifene on arterial thrombosis in ovariectomized mice. Menopause 2008; 15: 98-104. 13. Vitseva O, Flockhart DA< Jin Y, Varghese S, Freedman JE. The effects of tamoxifen and its metabolites on platelet function and release of reactive oxygen intermediates. J Pharmacol Exp Ther 2005; 312: 1144-1150. 14. Kuiper GGJM, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA. Interaction ofestrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998; 139: 4252-4263. 15. Landolfi R, Mower RL, Steiner M. Modification of platelet function and arachidonic acid metabolism by bioflavonoids: Structure-activity relations. Biochem Pharmacol 1984; 33: 1525-1530. 16. Nakashima S, Koike T, Nozawa Y. Genistein, a protein tyrosine kinase inhibitor, inhibits thromboxane A2-mediated human platelet responses. Mol Pharm 1991; 39: 475-480. 17. McNiol A. The effects of genistein on platelet function are due to thromboxane receptor antagonism rather than inhibition of tyrosine kinase. Prostaglandins Leukot Essent Fatty Acids 1993; 48: 379-384. |
| Project Title: | Nitric oxide signaling pathway involved in the inhibition of the release of endothelium-derived contracting factor in hypertension |
| Investigator(s): | Leung SWS |
| Department: | Pharmacology |
| Source(s) of Funding: | Travel Grants for NSFC/RGC JRS |
| Start Date: | 12/2009 |
| Abstract: |
| Travel grants for NSFC/RGC JRS |
| Project Title: | The influence of gender on endothelial senescence and dysfunction in Apolipoprotein E-deficient mice: role of sirtuin and telomerase |
| Investigator(s): | Leung SWS, Man RYK |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 12/2009 |
| Abstract: |
| Background Atherosclerosis is associated with hypercholesterolemia and is one of the primary pathology that accounts for cardiovascular morbidity and mortality. With intake of high cholesterol diet, premature senescence (permanent growth arrest) of endothelial cells occurred [1]. Senescent endothelial cells are characterised by an enlarged and flattened morphology, and by an increased activity of senescence-associated -galactosidase [2,3]. As endothelial cells senescent, they cannot function in an optimal way [4-6], with reduced activity of endothelial NO synthase (eNOS) and increased expression of intercellular adhesion molecule (ICAM-1) [7,8]. This endothelial dysfunction is manifested by an imbalance of release of relaxing and contracting factors [9,10]. Current consensus recognizes nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) as two major relaxing factors responsible for mediating endothelium-dependent relaxation [11,12], while the release of endothelium-derived contracting factor (EDCF) synthesized by the cyclooxygenases serves as one of the most obvious markers of severe endothelial dysfunction [13,14]. Estrogen has been shown to reduce the development of atherosclerosis in ovariectomized animals [15,16]. As senescence of the endothelium is considered an independent risk factor for the development of atherosclerosis [17,18], the atheroprotective effect of estrogen may be, at least partially, attributed to its ability to protect the endothelium against senescence. Endothelial senescence can be prevented by enhancing the telomerase activity through the introduction of the telomerase catalytic component (TERT) [7], and estrogen is one of the physiological regulators of the transcription of TERT [19,20]. Experimentally, increase in telomerase activity in human umbilical vein endothelial cells was prevented when the nicotinamide adenine dinucleotide-dependent histone deacetylase, sirtuin (Sirt1), was inhibited [21]. Over-expression of Sirt1 was effective in preventing the senescence of human umbilical vein endothelial cells [8, 21], and in reducing the degree of atherosclerosis in apolipoprotein E (ApoE)-deficient mice that were fed with high-fat diet for 10 weeks [22]. These observations, thus, implicated a role of Sirt1 in the development of endothelial senescence and hence atherosclerosis. Hypothesis: In view of the activity of estrogen on telomere function and the relationship between telomerase activity and endothelial sencesence, we hypothesize that females may be protected against the development of endothelial dysfunction, and hence the progression of atherosclerosis, in response to high cholesterol intake. Together with the indication that Sirt1 plays a role in the telomerase activity and/or endothelial senescence, the gender difference on the development of endothelial senescence, if present, may be related to the increases in the expression and/or activity of Sirt1 and /or TERT. Key issues and problem addressed: i. The influence of gender and ages on the senescence of endothelial cells will be studied in the aorta and mesenteric artery that are isolated from apolipoprotein E-deficient mice and its wildtype counterparts. ii. The degree of endothelial dysfunction and atherosclerotic lesion will be examined in the aorta and mesenteric artery with different stages of endothelial senescence, in order to determine whether or not there is a gender difference in the correlation, if any, between endothelial senescence and endothelial function/atherosclerotic development. iii. The expression and the activity of Sirt1 and TERT in the endothelium of the aorta and mesenteric artery with different stages of senescence will be measured. This findings will indicate whether or not Sirt1 and/or TERT plays a role in the progression of endothelial senescence in response to high cholesterol and whether or not their expressions and/or activities are affected by gender. Reference: [1] Shi Q, Hubbard GB, Kushwaha RS, Rainwater D, Thomas CA 3rd, Leland MM, Vandeberg JL, Wang XL. Am J Physiol Heart Circ Physiol 2007; 292: H2913-H2920. [2] Van der Loo B, Fenton MJ, Erusalimsky JD. Exp Cell Res 1998; 241: 309-315. [3] Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J. Proc Natl Acad Sci 1995; 92: 9363-9367. [4] Marin J. Age-related changes in vascular responses: a review. Mech Ageing Dev 1995; 79: 71-114. [5] Marin J, Rodriguez-Martinez MA. Exp Gerontol 1999; 34: 503-512. [6] Brandes RP, Fleming I, Busse R. ECardiovasc Res 2005; 66: 286-294. [7] Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Circulation 2002;105:1541–4. [8] Ota H, Akishita M, Eto M, Iijima K, Kaneki M, Ouchi Y. J Mol Cell Cardiol 2007; 571-579 [9] Vanhoutte PM. Eur Heart J 1997; 18 Suppl E: E19-E29. [10] Feletou M, Vanhoutte PM. Am J Physiol Heart Circ Physiol 2006; 291: H985-H1002. [11] Palmer RMJ, Ferrige AG, Moncada S. Nature 1987; 327: 524-526. [12] Chen G, Suzuki H, Weston AH. Br J Pharmacol 1988; 95: 1165-1174. [13] Koga T, Takata Y, Kobayashi K, Takishita S, Yamashita Y, Fujishima M. Hypertension 1989; 14: 542-548. [14] Heymes C, Habib A, Yang D, Mathieu E, Marotte F, Samuel J, Boulanger CM. Br J Pharmacol 2000; 131: 804-810. [15] Hodgin JB, Maeda N. Endocrinology 2002; 143: 4495-4501. [16] Bourghardt J, Bergstrom G, Kretek A, Sjoberg S, Boren J, Tivesten A. Endocrinology 2007; 148: 4128-4132. [17] Fenton M, Huang HL, Hong Y, Hawe E, Kurz DJ, Erusalimsky JD. Exp Gerontol 2004; 39: 115-122. [18] Minamino T, Komuro I. Circ Res 2007; 100: 15-26. [19] Grasselli A, Nanni S, Colussi C, Aiello A, Benvenuti V, Ragone G, Moretti F, Sacchi A, Bacchetti S, Gaetano C, Capogrosi MC, Pontecorvi A, Farsetti A. Circ Res 2008; 103: 34-42. [20] Farsetti A, Grasselli A, Bacchetti S, Gaetano C, Capogrossi MC. J Appl Physiol 2009; 106: 333-337. [21] Ota H, Eto M, Kano MR, Ogawa S, Iijima K, Akishita M, Ouchi Y. Arterioscler Thromb Vasc Biol 2008; 28: 1634-1639. [22] Zhang Q-J, Wang Z, Chen H-z, Zhou S, Zheng W, Liu G, Wei Y-s, Cai H, Liu D-p, Lian C-c. Cardiovasc Res 2008; 80: 191-199. |
| List of Research Outputs |
| Lau Y.T., Leung S.W.S. and Man R.Y.K., Potentiation of Kaempferol on Sodium Nitroprusside-induced Relazation in Porcine Coronary Arteries, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.09. |
| Lau Y.T., Leung S.W.S. and Man R.Y.K., The Flavonoid Kaempferol Enhances Sodium Nitroprusside-Induced Relaxation in Porcine Coronary Arteries Via Activation of Potassium Channels, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 69. |
| Leung S.W.S., Zhu D.-.Y. and Man R.Y.K., Effects of the aqueous extract of Salvia Miltiorrhiza (danshen) and its magnesium tanshinoate B-enriched form on blood pressure, Phytotherapy Research. 2009, 28: 769-774. |
| Leung S.W.S., Sun Yat Sen Foundation Fund for Academic Exchanges with China: Outgoing Visitorship , Sun Yat Sen Foundation Fund Committee of Management. 2009. |
| Liang C., Au A.L.S., Leung S.W.S., Ng J.K.F., Feletou M., Kwan Y.W., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-Derived Nitric Oxide Inhibits the Relaxation of the Porcine Coronary Artery to Natriuretic Peptides by Desensitizing Big Conductance Calcium-Activated Potassium Channels of Vascular Smooth Muscle, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334(1): 223-231. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-derived nitric oxide inhibits the relaxation to CNP in the porcine coronary artery, 13th Research Postgraduate Symposium, December 10-11, 2008. 2009. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Inhibition of the relaxation to CNY by endothelium-derived nitric oxide in the porcine coronary artery, Twelfth Annual Scientific Meeting of Institute of Cardiovascular Science and Medince, December 13-14, 2008, Hong Kong. 2009. |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Binding of Genistein with Membrane Estrogen Receptor and the Potentiating Effect of Genistein in Rapid, Non-Genomic Vascular Action, Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009. Hong Kong. Journal of the Hong Kong College of Cardiology.. 2009, 17(2): 53. |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, Non-genomic Vascular Actions of Genistein Involves a G-protein Coupled Receptor., 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.08. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Beneficial vascular effect of a non-selective PPAR activator in aorta of spontaneously hypertensive rats, Experimental Biology 2010, Anaheim, CA, USA. 2010. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Chronic Inhibition of Nitric-Oxide Synthase Potentiates Endothelium-Dependent Contractions in the Rat Aorta by Augmenting the Expression of Cyclooxygenase-2, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334,No.2: 373-380. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Differential Effects of PPAR Agonists on Vascular Reactivity in Aortas of Spontaneously Hypertensive Rats, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Researcher : Li AH |
| List of Research Outputs |
| Li A.H., Molecular and Cellular Mechanism Underlying Adipocyte Fatty Acid-binding Protein Expression Induced by LPS in Macrophages, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.12. |
| Researcher : Li H |
| List of Research Outputs |
| Hui X., Lam K.S.L., Wang Y., Xu A., Li H., Vanhoutte P.M.G.R. and Wu D., Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1., The Journal of Biological Chemistry. the United States, American Society for Biochemistry and Molecular Biology, 2010, 285: 10273. |
| Researcher : Li RWS |
| List of Research Outputs |
| Ho Y.W., Sit S.M., Li R.W.S., Kwan Y.W. and Leung G.P.H., Involvement of Plasma Membrane Monoamine Transporter in Serotonin Uptake in Vascular Smooth Muscle Cells, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 67. |
| Li R.W.S., Kwan Y.W. and Leung G.P.H., Effects of abacavir on the vascular and platelet activities., XX World Congress ISHR 2010 Kyoto, Japan. May 13-16, 2010.. 2010, P-2-18-6. |
| Li R.W.S., Kwan Y.W. and Leung G.P.H., Relationship between abacavir and Risk Factors of Cardiovascular Diseases, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 65. |
| Researcher : Li WSR |
| List of Research Outputs |
| TY L.A.M., SW S.E.T.O., AL A.U., CC P.O.O.N., Li W.S.R., HY L.A.M., WS L.A.U., SW C.H.A.N., SM N.G.A.I., Leung G.P.H., SM L.E.E., SK T.S.U.I. and YW K.W.A.N., Folic acid supplementation modifies beta-adrenoceptor-mediated in vitro lipolysis of obese/diabetic (+db/+db) mice, Experimental biology and medicine (Maywood, N.J.). 2009, 234(9): 1047-1055. |
| Researcher : Li Z |
| List of Research Outputs |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., Contractions of the SHR Aorta to High Doses of Epigallocatechin Gallate are Due to Vasoconstrictor Prostanoids, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(960.2). |
| Li Z. and Vanhoutte P.M.G.R., High Concentration of Epigallocatechin Gallate Induces Contractions of the Rat Aorta due to Production of Reactive Oxygen Species, Activation of Cyclooxygenase, Production of Prostanoids and Stimulation of Thromboxane-prostanoid Receptor, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.13. |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., High Concentrations Of Epigallocatechin Gallate Induce Contractions Of The Rat Aorta Due To Production Of Reactive Oxygen Species, Activation Of Cyclooxygenase, Production Of Prostanoids And Stimulation Of TP-Receptors, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 58. |
| Researcher : Liang C |
| List of Research Outputs |
| Liang C., Au A.L.S., Leung S.W.S., Ng J.K.F., Feletou M., Kwan Y.W., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-Derived Nitric Oxide Inhibits the Relaxation of the Porcine Coronary Artery to Natriuretic Peptides by Desensitizing Big Conductance Calcium-Activated Potassium Channels of Vascular Smooth Muscle, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334(1): 223-231. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-derived nitric oxide inhibits the relaxation to CNP in the porcine coronary artery, 13th Research Postgraduate Symposium, December 10-11, 2008. 2009. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Inhibition of the relaxation to CNY by endothelium-derived nitric oxide in the porcine coronary artery, Twelfth Annual Scientific Meeting of Institute of Cardiovascular Science and Medince, December 13-14, 2008, Hong Kong. 2009. |
| Liang C., Xu A. and Vanhoutte P.M.G.R., Toll-Like Receptor 4 Deficiency Attenuates Insulin Resistance And Endothelial Dysfunction Associated With Obesity And Diabetes In Mice, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 51. |
| Liang C., Xu A. and Vanhoutte P.M.G.R., Toll-like Receptor 4 Deficiency Attenuates Insulin Resistance and Endothelial Dysfunction Associated with Obesity and Diabetes in Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(571.5). |
| Liu T.C., Xu A., Lam K.S.L., Man R.Y.K., Vanhoutte P.M.G.R., Mak T.W., Law K.M., Tse H.F., Liang C. and Wang Y., Endothelial Dysfunctions Induced by Aging and Diet-induced Obesity is Attenuated in Lipocalin-2 Knockout Mice, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.16. |
| Liu T.C., Xu A., Man R.Y.K., Mak T.W., Law K.M., Liang C., Vanhoutte P.M.G.R. and Wang Y., Endothelium-dependent Contractions Induced by Aging and Diet-induced Obesity are Attenuated in Lipocalin-2 Deficient Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(570.3). |
| Researcher : Liang Y |
| List of Research Outputs |
| Zu Y., Liu L.I.N.G., Lee M.Y.K., Xu C., Liang Y., Man R.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells, Circulation Research. 2010, 106: 1384-1393. |
| Researcher : Lin AHY |
| List of Research Outputs |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Binding of Genistein with Membrane Estrogen Receptor and the Potentiating Effect of Genistein in Rapid, Non-Genomic Vascular Action, Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009. Hong Kong. Journal of the Hong Kong College of Cardiology.. 2009, 17(2): 53. |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, Non-genomic Vascular Actions of Genistein Involves a G-protein Coupled Receptor., 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.08. |
| Researcher : Liu TC |
| List of Research Outputs |
| Law K.M., Xu A., Lam K.S.L., Liu T.C., Berger T., Mak T.W., Zhang M.X.M. and Wang Y., Lipocalin 2-deficiency Attenuates Insulin Resistance Induced by High Fat Diet and Aging through Regulation of Lipid Metabolism and Inflammation in Adipose Tissue, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.06. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T., Vanhoutte P.M.G.R., Liu T.C., Sweeney G. and Wang Y., Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity., Diabetes. 2010, 59: 872-82. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T.W., Liu T.C., Sweeney G., Zhou M. and Wang Y., Mice Lacking Lipocalin-2 are Protected from Developing Insulin Resistance Associated with Aging and Obesity, 45th Annual Meeting of The European Association for the Study of Diabetes, September 29-October 2, 2009. Vienna - Austria. Diabetologia 2009. 52 supp:1: S20. |
| Liu T.C., Xu A., Lam K.S.L., Man R.Y.K., Vanhoutte P.M.G.R., Mak T.W., Law K.M., Tse H.F., Liang C. and Wang Y., Endothelial Dysfunctions Induced by Aging and Diet-induced Obesity is Attenuated in Lipocalin-2 Knockout Mice, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.16. |
| Liu T.C., Xu A., Man R.Y.K., Mak T.W., Law K.M., Liang C., Vanhoutte P.M.G.R. and Wang Y., Endothelium-dependent Contractions Induced by Aging and Diet-induced Obesity are Attenuated in Lipocalin-2 Deficient Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(570.3). |
| Researcher : Mak JCW |
| Project Title: | Role of transforming growth factor-beta1 variants in susceptibility to tuberculosis in Hong Kong Chinese population |
| Investigator(s): | Mak JCW, Chan MMW |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 02/2005 |
| Abstract: |
| i) To study the role of two common single nucleotide polymorphisms (SNPs) at the promoter (C-509T) and coding regions (T869C) of the TGF-beta1 gene in conferring susceptibility to the development of tuberculosis (TB) in Hong Kong Chinese population. ii) To perform functional analysis in correlating the associated polymorphisms with the plasma level of TGF-beta1 in TB patients and healthy controls. iii) To conduct a study in determining the proportion of patients with chronic obstructive pulmonary disease (COPD) with a past history of tuberculosis since COPD is a major cause of respiratory disability in Hong Kong. |
| Project Title: | Effects of intermittent hypoxia and/or cigarette smoke on oxidative stress-induced apoptotic markers in human endothelial cells |
| Investigator(s): | Mak JCW, Ip MSM |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 04/2008 |
| Completion Date: | 09/2009 |
| Abstract: |
| Obstructive sleep apnoea (OSA) is an increasingly common disorder. Including “subclinical” subjects who do not claim overt symptoms, the condition is estimated to affect as many as a quarter of the middle-aged men in some Caucasian populations, and at least 8% of Chinese men in Hong Kong [1,2]. It is a condition characterized by repeated interruptions in the airflow due to partial or complete collapse of the upper airway during sleep, leading to chronic intermittent hypoxia (CIH). There is growing evidence that it may constitute an independent risk factor for cardiovascular disease (CVD)[3]. Cigarette smoking is a well-established cardiovascular risk factor [4]. It has been reported that cigarette smoking (CS) is independently associated with an increased risk of OSA [5], and smoking is not an uncommon prevailing habit among OSA subjects, depending on the smoking prevalence of the population as well. It is highly plausible that OSA and cigarette smoking both contribute independently as well as interact in vascular pathogenesis. Recently, a synergistic effect has been reported between OSA and cigarette smoking (CS) on some of the biochemical cardiovascular risk markers such as ceruloplasmin and high density lipoprotein (HDL)[6]. The mechanistic pathways leading to vascular dysfunction in OSA or CS exposure, and in particular their potential interactions have not been fully elucidated. Endothelial cells provide a permeable barrier between circulating blood cells and the underlying vascular tissue, and play a pivotal role in the regulation of vascular tone and cellular growth. Endothelial cell homeostasis is maintained by balancing proliferation and apoptosis. Increased detection of endothelial apoptotic cells has been reported ex vivo in patients with OSA[7]. Endothelial cell apoptosis has also been implicated in smoking-related endothelial dysfunction [8], in which cigarette smoke induces necrosis of endothelial cells [9]. In both OSA and CS, there is now evidence that oxidative stress may be important intermediary mechanisms of endothelial injury. In OSA, the repetitive periods of hypoxia and reoxygenation may promote cell stress, while cigarette smoke contains a large number of different oxidants and radicals that are known to cause a pro-oxidative state in the circulating system [10]. We hypothesize that either intermittent hypoxia (IH) or cigarette smoke (CS) exposure could increase endothelial cell death through Bcl-2/Bax expression, and the combined exposure would be additive or synergistic. The Bcl-2 family of protein comprising both anti- and pro-apoptotic members plays pivotal roles in regulating apoptosis [11]. The 26 kDa Bcl-2 membrane-associated antiapoptic member who prevents apoptosis and necrotic death by inhibiting the release of cytochrome c from the mitochondria [12]. In contrast Bax, the binding partner protein for Bcl-2 [13], mainly induces cytochrome c release from mitochondria [14]. Actually, the balance of Bcl-2/Bax in a cell is regarded as one of the crucial factors determining whether or not the cell will undergo apoptosis. Objectives The specific aims of the study are: · To construct a novel in vitro endothelial cell system to explore features of apoptosis underlying the molecular response in cultured cells exposed to IH and CS. · To characterize whether IH- and/or CS-induced alterations in O2·- and H2O2 production play a role in apoptosis. · To examine the effects of IH and CS on proteins of Bcl-2 family. References 1. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. A population health perspective. Am J Respir Crit Care Med 2002;165:1217-1239. 2. Ip MS, Lam B, Tang LC, Lauder IJ, Ip TY, Lam WK. A community study of sleep-disordered breathing in middle-aged Chinese women in Hong Kong. Chest 2004;125:127-134. 3. McNicholas WT, Bonsignore MR. Sleep apnea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;129:156-178. 4. Barnoya J, Glantz SA. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005;111:2684-2698. 5. Kashyap R, Hock LM, Bowman TJ. Higher prevalence of smoking in patients diagnosed as having obstructive sleep apnea. Sleep Breath 2001;5:167-172. 6. Lavie L, Lavie P. Smoking interacts with sleep apnea to increase cardiovascular risk. Sleep Med 2007 May 18 [Epub ahead of print] 7. El Solh AA, Akinnusi ME, Baddoura FH, Mankowski CR. Endothelial cell apoptosis in obstructive sleep apnea. A link to endothelial dysfunction. Am J Respir Crit Care Med 2007;175:1186-91. 8. Yang YM, Liu GT. Damaging effect of cigarette smoke extract on primary cultured human umbilical vein endothelial cells and its mechanism. Biomed Environ Sci 2004;17:121-34. 9. Wickenden JA, Clarke MC, Rossi AG, Rahman I, Faux SP, Donaldson K, MacNee W. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. Am J Respir Cell Mol Biol 2003;29:562-70. 10. Bernhard D, Wang XL. Smoking, oxidative stress and cardiovascular diseases – do anti-oxidative therapies fail? Curr Med Chem 2007;14:1703-1712. 11. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;81:1322-1326. 12. Kuwana T, Newmeyer DD. Bcl-2 family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 2003;15:691-699. 13. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609-619. 14. Jurgensmeier JM, Xie Z, Deveraux Q et al. Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 1998;95:4997-5002. |
| Project Title: | Effects of intermittent hypoxia and/or cigarette smoking on endothelial injury in vivo - relevant to obstructive sleep apnea |
| Investigator(s): | Mak JCW, Ip MSM |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 10/2008 |
| Abstract: |
| (1) To set up an in vivo experimental rat model of exposure to CIH in OxyCycler A84 System and/or exposure to CS in a specially designed smoking chamber; (2) To compare the vascular morphological changes over time (4, 8 and 12 weeks) in rats exposed to CIH and/or CS; (3) To evaluate apoptotic markers in serum and/or vascular tissues in this rat model; (4) To determine the oxidative/antioxidative, and inflammatory/anti-inflammatory status in serum and/or vascular tissues in this rat model; (5) To study endothelial dysfunction in clinical subjects (measuring peripheral arterial tone response to reactive hyperemia; and circulating biomarkers of interest), with reference to their OSA and smoking status. |
| Project Title: | Pre- and post-operation sputum and serum tumor markers in non-small cell lung cancer patients |
| Investigator(s): | Mak JCW, Lam B |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 04/2009 |
| Abstract: |
| Lung cancer is the leading cause of cancer mortality with a 5-year survival of 14% (1). In Hong Kong, it accounts for about 30% of all cancer death (2). For patients with early stage non-small cell lung cancer (stage I or II), surgery provides the best prospect of cure with 5 year survival ~ 70%. Despite curative operation, clinically significant second primary lung cancer is diagnosed in patients with prior NSCLC at a rate of 1 to 3% per patient per year (3-5). Despite postoperative follow-up, only 50% of second primary lung cancers are resectable either due to late presentation or limited lung reserve. Routine postoperative chest roentgenograms (CXR) are neither sensitive nor specific for detection of second lung cancer. Computed tomography (CT) is superior to CXR in detecting parenchymal nodules but CT is not sensitive in detecting early endobronchial lesions. Newer bronchoscopy systems are able to detect early endobronchial lesions (7) but because of the invasive nature of the bronchoscopy, this is unlikely a primary tool for early detection of lung cancer. As lung cancer arises from the epithelium of the bronchial tree, sputum examination could be the earliest way of detecting lung cancer non-invasively. Sputum cytology, however, has a low sensitivity for peripheral lung cancer, i.e. adenocarcinoma, the commonest type of lung cancer (8). It has been showed that respiratory secretions from lung cancer patients contained high levels of tumor markers (9).By using micro sampling probe tools (which can collect bronchial epithelial lining fluid), tumor markers in fluid from tissues surrounding lung cancer are significantly higher than that of the contra lateral sides and that of the corresponding serum level (10). However, the technology still needs to be applied via bronchoscopy, i.e. invasively. A recent published paper demonstrated that tumor markers from induced sputum were significantly higher in lung cancer patients suggesting tumor markers in the sputum could be used as a tool for early detection of lung cancer (11). We hypothesize that sputum tumor markers would have a good correlation with lung cancer status and could be used as a clinical tool for early detection of second primary lung cancer in patients with cured non-small cell lung cancer (NSCLC) patients. This could improve the prognosis of lung cancer. Objectives • To evaluate carcinoembryonic antigen (CEA) and cytokeratin fragment 19 (CYFRA 21-1) levels in sputum and serum before operation, 3 months and 1 year after operation • To compare the diagnostic utility of sputum with that of serum tumor markers References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999;49:8-31. 2. Hong Kong Cancer Registry: Cancer Incidence & Mortality in Hong Kong. Hospital Authority 1999. 3. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335-1345. 4. Thomas PA, Rubinstein L. Malignant disease appearing late after operation for T1 N0 non-small cell lung cancer. J Thorac Cardiovsc Surg 1993;106:1053-1058. 5. Woolner LB, Fontana RS, Cortese DA, et al. Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 1984;59:453-466. 6. Athanassiadou P, Psyhoyou H, Kyrkou K et al. Expression of keratins and carcinoembryonic antigen in bronchial squamous metaplasma and lung carcinomas. Acta Cytol 1995;39:1161-1166. 7. Lam S et al. Fluorescence tumor detection, in Hetzel MR (ed): Minimally invasive Techniques in Thoracic Medicine and Surgery; pp 179-191. London, Chapman & Hall, 1995. 8. Kennedy TC, Hirsch FR. Using molecular markers in sputum for the early detection of lung cancer: a review. Lung Cancer 45(Suppl 2): S21-S27. 9. Khajotia RR, Mohn A, Pokieser L et al. Induced sputum and cytological diagnosis of lung cancer. Lancet 1991;338:976-977. 10. Watanabe M, Ishizaka A, Ikeda E, Ohashi A, Kobayashi K. Contributions of Bronchoscopic Microsampling in the Supplemental Diagnosis of Small Peripheral Lung Carcinoma Ann Thorac Surg 2003;76:1668 –73 11. Hillas G, Moschos C, Dimakou K et al. Carcinoembryonic antigen, neuron-specific enolase and cytokeratin fragment 19 (CYFRA 21-1) levels in induced sputum of lung cancer patients. Scandinavian Journal of Clinical and Laboratory Investigation, 2008;68:542-547 |
| Project Title: | Involvement of serotoninergic system in cigarette smoke-induced inflammatory responses in human airway epithelial cells |
| Investigator(s): | Mak JCW |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 05/2010 |
| Abstract: |
| Background Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway limitation together with abnormal inflammation in the lung. Cigarette smoke (CS) is one of the major causes to this disease, which is involved in the induction of inflammatory responses in the airway by elevating pro-inflammatory cytokines, i.e. interleukin-8 (IL-8). As the first site of contacting CS, airway epithelial cells play an important role in monitoring the airway inflammation process. Exposure to CS has been reported to elevate interleukin-8 (IL-8) release in epithelial cells which is positively correlated to airway dysfunction (1). Serotonin (5-hydroxytryptamine; 5-HT) is a neuroimmunomodulator which is present in brain and peripheral tissues. 5-HT has a variety of physiological functions including regulation of temperature, learning and memory, and can affect the activities of the gastrointestinal tract, the cardiovascular and respiratory systems. 5-HT is released during inflammatory processes and may interact with circulating immune cells. Evidences such as increased systemic serotonin levels in non-smokers after smoking (2) and improved lung function by applying selective serotonin receptor 2 antagonist, ketanserin, to COPD patients (3,4), suggest the involvement of serotoninergic system in COPD. Recently, activation of 5-HTR subtypes with selective 5-HTR agonists elevates the release of pro-inflammatory markers, IL-6 and IL-8, in BEAS-2B and alveolar epithelial cells type II (AEC-II), further indicating the involvement of peripheral serotoninergic system in lung epithelial inflammation process (5). Of the 7 different 5-HT receptor families (5-HTR1-7), each of these are G-protein-coupled receptors with the exception of the 5-HTR3, which is a ligand-gated ion channel (6). 5-HTR2 including 5-HTR2A, 5-HTR2B and 5-HTR2C, has been shown in regulating inflammatory responses in different cell types (7-9). Activation of 5-HTR2A can result in stimulating mitogen-activated protein kinases (MAPKs) signaling cascade via inositol 1, 4, 5-triphosphate (IP3) and diacylglycerol pathways (10-13). MAPKs, including p38, extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminus kinase (JNK), have recently been shown to be involved in cigarette smoking elicited IL-8 release in human cultured epithelial cells (14). Nevertheless, the presence of serotonin itself has been demonstrated to be necessary for expression of the inflammatory markers IL-6 and TNF-α, with lower serotonin levels inducing, and higher levels decreasing, expression of these markers (15). This inverted U-shaped response clearly indicates that serotonin may play an important role in modulating molecular components of the inflammatory process. Rationale for the proposed study It is unclear whether exposure to CS will release 5-HT from airway epithelial cells in the modulation of IL-8 release. We hypothesize that activation of 5-HT2 receptors may contribute to CS-induced IL-8 release via MAPK signaling pathways in human airway epithelial cells. The proposed study is designed to address these important issues in the inflammatory process. A better understanding of these mechanisms may aid us in providing potential platforms for novel therapies in CS-induced lung diseases such as COPD. Objectives • To study whether CS-induced 5-HT causes pro-inflammatory IL-8 release • To investigate the mechanisms on how CS modulates the 5-HT levels leading to IL-8 release References 1. Kodama T, Kanazawa H, Tochino Y, Kyoh S, Asai K, Hirata K. A technological advance comparing epithelial lining fluid from different regions of the lung in smokers. Respir Med 2009; 103:35-40. 2. Racké K, Schwörer H, Simson G. Effects of cigarette smoking or ingestion of nicotine on platelet 5-hydroxytryptamine (5-HT) levels in smokers and non-smokers. Clin Investig 1992; 70:201-204. 3. Cazzola M, D’Amato G, Lobefalo G, Guillaro B, Sepe J, Assogna G, Pietroletti R, Lauria D. Ketanserin, a new blocking agent of serotonin S2-receptors. Respiratory functional effects in chronic obstruction of the airways. Chest 1987; 92:863-866. 4. Cazzola M, Guidetti E, Sepe J, Assogna G, Lucchetti G, Santangelo G, D'Amato G. Acute respiratory and cardiovascular effects of inhaled ketanserin in chronic obstructive pulmonary disease. A comparative study with intravenously administered ketanserin. Chest 1990; 97:901-905. 5. Bayer H, Müller T, Myrtek D, Sorichter S, Ziegenhagen M, Norgauer J, Zissel G, Idzko M. Serotoninergic receptors on human airway epithelial cells. Am J Respir Cell Mol Biol 2007; 36:85-93. 6. Nichols DE, Nichols CD. Serotonin receptors. Chem Rev 2008; 108:1614-1641. 7. Ito T, Ikeda U, Shimpo M, Yamamoto K, Shimada K. Serotonin increases interleukin-6 synthesis in human vascular smooth muscle cells. Circulation 2000; 102:2522-2527. 8. Cloez-Tayarani I, Petit-Bertron A-F, Venters HD, Cavaillon J-M. Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors. Int Immunol 2003; 15:233-240. 9. Marconi A, Darquenne S, Boulmerka A, Mosnier M, D’Alessio P. Naftidrofuryl-driven regulation of endothelial ICAM-1 involves nitric oxide. Free Rad Biol Med 2003; 34:616-625. 10. Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B, and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 1999; 128:13-20. 11. Greene EL, Houghton O, Collinsworth G, Garnovskaya MN, Nagai T, Sajjad T, Bheemanathini V, Grewal JS, Paul RV, Raymond JR. 5-HT2A receptors stimulate mitogen-activated protein kinase via H2O2 generation in rat renal mesangial cells. Am J Physiol Renal Physiol 2000; 278:F650-F658. 12. Jerman JC, Brough SJ, Gager T, Wood M, Coldwell MC, Smart D, Middlemiss DN. Pharmacological characterization of human 5-HT2 receptor subtypes. Eur J Pharmacol 2001; 414:23-30. 13. Knauer CS, Campbell JE, Chio CL, Fitzgerald LW. Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors. Naunyn-Schmied Arch Pharmacol 2009; 379:461-471. 14. Moretto N, Facchinetti F, Southworth T, Civelli M, Singh D, Patacchini R. α,-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol 2009; 296:L839-L848. 15. Kubera M, Maes M, Kenis G, Kim YK, Lason W. Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6. Psychiartry Res 2005; 134:251-258. |
| List of Research Outputs |
| Chan C.K.Y., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., Nitric Oxide Synthase and Soluble Guanylyl Cyclase Activation are Required for Hypoxic Endothelium-Dependent Contractions of the Porcine Coronary Artery, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(957.2). |
| Researcher : Man RYK |
| Project Title: | Gender differences in the regulation of endothelium-dependent contracting factor |
| Investigator(s): | Man RYK, Vanhoutte PMGR, Leung SWS |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2006 |
| Completion Date: | 08/2009 |
| Abstract: |
| (1) Gender differences exist in the production and/or actions of EDCF, in particular in hypertensive and aging rats. This different between male and female are caused by the non-genomic action of the major female hormone, estrogen. (2) Estrogen modulates the changes in the key proteins that are involved in the production and the action of EDCF in arteries from hypertensive and aging rats. Examples of these proteins are muscarinic receptor(s) in endothelial cells, prostanoid receptors in vascular smooth muscle cells and prostanoid synthase(s) in both cell types. (2) The activation of soluble guanylyl cyclase in endothelial cells has an autocrine effect to diminish the activity and/or expression of prostanoid synthase(s) resulting in inhibition of the production of EDCF. The extent of activation of this enzyme is influenced by the hormonal status of rats. |
| Project Title: | Mechanism for the modulation of vascular function by flavonoids |
| Investigator(s): | Man RYK, Leung GPH, Leung SWS |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2007 |
| Abstract: |
| (1) Flavonoids mimic selectively the vascular but not the hormonal effects of 17beta-estradiol. These benefical vascular actions of flavonoids are mediated through the same signaling cascade as 17beta-estradiol; (2) Modulation of vascular reactivity by flavonoids is affected by gender, and is influenced by the hormonal status; (3) That certain flavonoids such as kaempferol with the ability to enhance endothelium-dependent and -independent relaxations act via mechanisms distinct from the genomic actions of 17beta-estradiol. |
| Project Title: | Outstanding Research Student Supervisor Award 2007-2008 |
| Investigator(s): | Man RYK |
| Department: | Pharmacology |
| Source(s) of Funding: | Outstanding Research Student Supervisor Award |
| Start Date: | 10/2008 |
| Abstract: |
| For recognizing, rewarding and encouraging exceptioal research achievements; and for strengthening the research culture of the University. |
| Project Title: | Effect of rutin, a flavonoid commonly found in diet, on the regulation of blood pressure in spontaneously hypertensive rats |
| Investigator(s): | Man RYK, Leung SWS |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 12/2008 |
| Completion Date: | 05/2010 |
| Abstract: |
| Flavonoids are polyphenolic compounds that exist widely in the plant kingdom. They are important components of many traditional Chinese medicine and phyto-medicine. Epidemiological reports have demonstrated an association between high dietary intake of flavonoids and lower incidence of heart diseases [1-3]. Among the daily intake of flavonoids, about 60-75% is quercetin [4,5]. Quercetin has been shown to possess antioxidant properties [6]. Furthermore, it has been demonstrated to induce concentration-dependent relaxation in both conductance and resistance arteries in different animal models [7-10]. All these effects of quercetin may contribute to the protective effects on the cardiovascular system. However, quercetin normally does not exist in its free form. Quercetin can exist in various conjugated forms and can be detected in the plasma of human and rat after ingestion of quercetin [11-13]. Moreover, quercetin is present in fruits and vegetables mainly as glycosides such as rutin [14,15]. The bioavailibity and pharmacokinetics of quercetin are very different to those of the glycosides. As such, studies using quercetin in isolated tissues may not represent the normal situation where rutin the conjugated form is the natural source of quercetin. The present study, therefore, proposes to examine the cardiovascular actions of rutin, a quercetin glycoside, following oral administration in rats. Specifically, changes in blood pressure in response to vasoactive substances, phenylephrine and acetylcholine, will be studied in rats administered orally with rutin for a short period of time. These responses in normal adult rats will be compared to those in hypertensive rats, with an aim to determine whether or not the effect of rutin on the regulation of blood pressure will be altered in rats with cardiovascular diseases. References: [1] Finkel E. Lancet 1998; 352:1762. [2] Knekt P, Kumpulainen J, Järvinen R, et al. Am J Clin Nutr 2002; 76: 560-568. [3] Jenkins DJA, Kendall CWC, D’Costa MA, et al. J Urol 2003; 169: 507-511. [4] Hertog MGL, Kromhout D, Aravanis C, Blackburn H, Buzina R, Fidanza F, Giampaoli S, Jansen A, Menotti A, Nedelijkovic S, Pekkarinen M, Simic BS, Toshima H, Peskens EJM, Hollman PCH, Katan MB. Arch Intern Med 1995; 155: 381-386. [5] Rimm EB, Katan MB, Ascherio A, Stamper MJ Willett WC. Ann Intern Med 1996; 125: 384-389. [6] Terao J, Piskula M, Yao Q. Arch Biochem Biophys 1994; 308: 278-284. [7] Duarte J, Perez-Vizcaino F, Utrilla P, et al. Gen Pharmacol 1993; 24: 857-862. [8] Perez-Vizcaino F, Ibarra M, Cogolludo AL, et al. J Pharmacol Exp Ther 2002: 302, 66-72. [9] Guerrero MF, Puebla P, Carrón R, et al. J Pharm Pharmacol 2002: 54; 1373-1378. [10] Fusi F, Saponara S, Pessina F, et al. Euro J Nutr 2003; 42: 10-17. [11] Gugler R, Leschik M, Dengler HJ. Eur J Clin Pharmacol 1975; 9: 229-234. [12] Manach C, Morand C, Demigne C, Texier O, Regerat F, Remesy C. FEBS Lett 1997; 409: 12-16. [13] Graefe EU, Wittig J, Mueller S, Riethling AK, Uehleke B, Drewelow B, Pforte H, Jacobasch G, Derendorf H, Veit M. J Clin Pharmacol 2001; 41: 492-499. [14] Hertog MG, Hollman PC, Katan MB, Kromhout D. Nutr Cancer 1993; 20: 21-29. [15] Justesen U, Knuthsen P, Leth T. Cancer Letters 1997; 114: 165-167. |
| Project Title: | Beneficial vascular effect of estrogen is medicated by the activation of GPR30 in endothelial and vascular smooth muscle cells |
| Investigator(s): | Man RYK, Leung SWS, Leung GPH |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 12/2009 |
| Abstract: |
| Background: Prior to menopause, women have a lower incidence of coronary heart disease (CHD) than age-matched men [1,2]. Estrogen replacement therapy reduces CHD mortality in post-menopausal women [3,4] although large scale clinical trials including women many years after menopause has no benefit. Studies in humans indicate that chronic [5,6] and acute [7] administration of 17β-estradiol enhance endothelium-dependent vasodilation. 17β-estradiol acts as a calcium antagonist [8] on voltage operated calcium channels [9,10]. It also stimulates nitric oxide (NO) release by activating soluble guanylyl cyclase and opening of calcium-activated potassium channels [11,12]. We have previously demonstrated that low concentrations of 17β-estradiol enhance endothelium-independent relaxation [13] and reduce agonist-induced contractions [14] in porcine coronary arteries via the cyclic AMP pathway [15,16]. Recent studies support that these vascular effects of estrogen are mediated by the putative membrane receptor and are different from the classical genomic effects of estrogen via cytosolic estrogen receptors. Currently, two estrogen receptor subtypes have been identified: the classical ERα and the more recently identified ERβ [17,18]. Both ERα and β receptors are expressed in the vascular system [19,20]. However, ERα did not appear to mediate the vascular action of estrogen, since 17β-estradiol produced similar vascular protection in ERα receptor knock-out mice compared to wild-type counterparts [21]. Moreover, only the expression of ERβ receptor mRNA was upregulated in rat arteries following vascular injury, whereas ERα receptor mRNA expression did not change [22,23]. Selective antagonist of classical estrogen receptor (ICI 164384 or ICI 182780) did not alter the relaxation to 17β-estradiol [13,24]. In mice with both ERα and ERβ knockout, part of the inhibiting response to vascular injury by estrogen was conserved [25]. This suggests the presence of an undefined receptor distinct from ERα and ERβ. Recently, evidence is accumulating for membrane-associated binding sites for 17β-estradiol that are independent of the classical genomic estrogen receptors [26,27]. GPR30, which is a G protein-coupled receptor, can be activated by 17β-estradiol and mediates rapid cellular responses [28,29]. However, it is not clear if the vascular actions of 17β-estradiol are mediated via GPR30. Aim of the study: Previous studies indicate that 17β-estradiol affects the synthesis of prostaglandins in the endothelium and vascular smooth muscle. 17β-estradiol also modulates the expression of cyclooxygenase-1 and cyclooxygenase-2 in the vascular tissue. GPR30 has been proposed as the membrane receptor for 17β-estradiol. Whether or not GPR30 mediates the vascular actions of 17β-estradiol is not clear. Recently, a selective agonist for GPR30, G-1, has been reported. With this agonist, it is possible to compare the vascular actions via the selective activation of GPR30 with G-1 and 17β-estradiol. Specifically we will compare the alteration in the synthesis of prostaglandins and in the expression of cyclooxygenases. Furthermore, G-1 although capable of activating GPR30 should have little or no hormonal effect via cytosolic ERα and ERβ receptors. Key issues and problem addressed: i. To examine the vascular effects resulted from the activation of GPR30 by G-1, and compare these effects to those of 17β-estradiol. ii. To investigate the involvement of GPR30 in the hormonal actions of 17β-estradiol. Reference: 1. Barrett-Connor E. Circulation 1997; 95: 252-264. 2. Van der Schouw YT, Van der Graaf Y, Steyerberg EW, et al. Lancet 1996; 347: 714-718. 3. Ettinger N, Friedman GD, Bush T, et al. Obstet Gynecol 1996; 87: 6-12. 4. Stampfer JM, Colditz FA, Willett WC, et al. N Engl J Med 1991; 325: 756-762. 5. Herrington DM, Braden GA, Williams JK, et al. Am J Cardiol 1994; 73: 951-952. 6. Gilligan DM, Quyyumi AA, Cannon RO. Circulation 1994; 89: 2545-2551. 7. Gilligan DM, Badar DM, Panza JA, et al. Circulation 1994; 90: 786-791. 8,. Han S-Z, Karaki H, Ouchi Y, et al. Circulation 1995; 91: 2619-2626. 9. Sudhir K, Chou TM, Mullen WL, et al. J Am Coll Cardiol 1995; 26: 807-814. 10. McCrohon JA, Walters WAW, Robinson JTC, et al. J Am Coll Cardiol 1997; 29: 1432-1436. 11. Rubanyi GM, Freay AD, Kauser K, et al. J Clin Invest 1997; 99: 2429-2437. 12. Caulin-Glaser T, Garcia-Cardena G, Sarrel P, et al. Circ Res 1997; 81: 885-892 13. Teoh H, Leung SWS, Man RYK. Cardiovas Res 1999; 42: 224-231. 14. Teoh H, Quan A, Leung SWS, Man RYK. Br J Pharmacol 2000a; 129: 1301-8. 15. Teoh H, Man RYK. Br J Pharmacol 2000; 129: 1739-47. 16. Keung W, Vanhoutte PM, Man RYK. Br J Pharmacol 2005; 144: 71-79. 17. Kuiper GGJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Proc Natl Acad Sci USA 1996; 93: 5925-5930. 18. Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J. Science 1986; 231: 1150-1154. 19. Hodges YK, Tung L, Yan XD, Graham JD, Horwitz KB, Horwitz LD. Circulation 2000; 101: 1792-1798. 20. Inoue S, Hoshino S, Miyoshi H, Akishita M, Hosoi T, Orimo H, Ouchi Y. Biochem Biophys Res Commun 1996; 219: 766-772. 21. Iafrati MD, Karas RH, Aronovitz M, Kim S, Sullivan TR Jr, Lubahn DB, O’Donnell TF Jr, Korach KS, Mendelsohn ME. Nature Med 1997; 3: 545-548. 22. Lindner V, Kim SK, Karas RH, Kuiper GGJM, Gustafsson JA, Mendelsohn ME. Circ Res 1998; 83: 224-229. 23. Makela S, Savolainen H, Aavik E, Myllarniemi M, Strauss L, Taskinen E, Gustafsson JA, Hayry P. Proc Natl Acad Sci USA 1999; 96: 7077-7082. 24. Freay AD, Curtis SW, Korach KS, Rubanyi GM. Circ Res 1997; 91: 242-248. 25. Karas RH. Schulten H, Pare G, Aronovitz MJ, Ohlsson C, Gustafsson JA, Mendelsohn ME. Cir Res 2001; 89: 534-539. 26. Nadal A, Ropero AB, Laribi O, Maillet M, Fuentes E, Soria B. Profc. Natl Acad Sci USA 2000; 97: 11603-11608. 27. Haynes MP, Li L, Russell KS, Bender JR. Vascul Pharmacol 2002; 38: 99-108. 28. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. Science 2005; 307: 1625-1630. 29. Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y. Biochem Biophys Res Comm 2006; 345: 904-910. |
| List of Research Outputs |
| Chan C.K.Y., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., Nitric Oxide Synthase and Soluble Guanylyl Cyclase Activation are Required for Hypoxic Endothelium-Dependent Contractions of the Porcine Coronary Artery, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(957.2). |
| Chan K.H., Ho S.P., Yeung S.C., So H.L., Cho C.H., Koo M.W.L., Lam W.K., Ip M.S.M., Man R.Y.K. and Mak J.C.W., Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine. 2009, 103: 1746-1754. |
| Chan K.H., Yeung S.C., Ip M.S.M., Man R.Y.K. and Mak J.C.W., Effects of Chinese green tea on cigarette smoke-induced lung inflammation, oxidative stress and protease activity in rats, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A5062. |
| Lau Y.T., Leung S.W.S. and Man R.Y.K., Potentiation of Kaempferol on Sodium Nitroprusside-induced Relazation in Porcine Coronary Arteries, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.09. |
| Lau Y.T., Leung S.W.S. and Man R.Y.K., The Flavonoid Kaempferol Enhances Sodium Nitroprusside-Induced Relaxation in Porcine Coronary Arteries Via Activation of Potassium Channels, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 69. |
| Leung S.W.S., Zhu D.-.Y. and Man R.Y.K., Effects of the aqueous extract of Salvia Miltiorrhiza (danshen) and its magnesium tanshinoate B-enriched form on blood pressure, Phytotherapy Research. 2009, 28: 769-774. |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., Contractions of the SHR Aorta to High Doses of Epigallocatechin Gallate are Due to Vasoconstrictor Prostanoids, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(960.2). |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., High Concentrations Of Epigallocatechin Gallate Induce Contractions Of The Rat Aorta Due To Production Of Reactive Oxygen Species, Activation Of Cyclooxygenase, Production Of Prostanoids And Stimulation Of TP-Receptors, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 58. |
| Liang C., Au A.L.S., Leung S.W.S., Ng J.K.F., Feletou M., Kwan Y.W., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-Derived Nitric Oxide Inhibits the Relaxation of the Porcine Coronary Artery to Natriuretic Peptides by Desensitizing Big Conductance Calcium-Activated Potassium Channels of Vascular Smooth Muscle, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334(1): 223-231. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-derived nitric oxide inhibits the relaxation to CNP in the porcine coronary artery, 13th Research Postgraduate Symposium, December 10-11, 2008. 2009. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Inhibition of the relaxation to CNY by endothelium-derived nitric oxide in the porcine coronary artery, Twelfth Annual Scientific Meeting of Institute of Cardiovascular Science and Medince, December 13-14, 2008, Hong Kong. 2009. |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Binding of Genistein with Membrane Estrogen Receptor and the Potentiating Effect of Genistein in Rapid, Non-Genomic Vascular Action, Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009. Hong Kong. Journal of the Hong Kong College of Cardiology.. 2009, 17(2): 53. |
| Lin A.H.Y., Leung G.P.H., Leung S.W.S. and Man R.Y.K., Rapid, Non-genomic Vascular Actions of Genistein Involves a G-protein Coupled Receptor., 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.08. |
| Liu T.C., Xu A., Lam K.S.L., Man R.Y.K., Vanhoutte P.M.G.R., Mak T.W., Law K.M., Tse H.F., Liang C. and Wang Y., Endothelial Dysfunctions Induced by Aging and Diet-induced Obesity is Attenuated in Lipocalin-2 Knockout Mice, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.16. |
| Liu T.C., Xu A., Man R.Y.K., Mak T.W., Law K.M., Liang C., Vanhoutte P.M.G.R. and Wang Y., Endothelium-dependent Contractions Induced by Aging and Diet-induced Obesity are Attenuated in Lipocalin-2 Deficient Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(570.3). |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Beneficial vascular effect of a non-selective PPAR activator in aorta of spontaneously hypertensive rats, Experimental Biology 2010, Anaheim, CA, USA. 2010. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Chronic Inhibition of Nitric-Oxide Synthase Potentiates Endothelium-Dependent Contractions in the Rat Aorta by Augmenting the Expression of Cyclooxygenase-2, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334,No.2: 373-380. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Differential Effects of PPAR Agonists on Vascular Reactivity in Aortas of Spontaneously Hypertensive Rats, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Chronic Treatment Of Vitamin D Derivatives Reduce Endothelium-Dependent Contractions In The Aorta Of The Spontaneously Hypertensive Rat, Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009. Hong Kong. Journal of the Hong Kong College of Cardiology.. 2009, 17(2): 53. |
| Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Vitamin D Derivatives Reduce Endothelium-dependent contractions in the Isolated Spontaneously Hypertensive Rat Aorta., 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Zu Y., Liu L.I.N.G., Lee M.Y.K., Xu C., Liang Y., Man R.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells, Circulation Research. 2010, 106: 1384-1393. |
| Researcher : Ng JKF |
| Project Title: | Effect of non-steroidal anti-inflammatory agents on platelet function and blood loss in patients undergoing major joint replacement surgery |
| Investigator(s): | Ng JKF, Chiu PKY, Tang WM |
| Department: | Anaesthesiology |
| Source(s) of Funding: | Queen Mary Hospital Charitable Trust - Training and Research Assistance Scheme |
| Start Date: | 10/2007 |
| Abstract: |
| To establish the correlation between PFA-100 measurement and blood loss during surgery, hopefully the results may help to establish the clinical usefulness of PFA-100 in monitoring patients with preoperative platelet dysfunction or those who are taking anti-platelet medications before surgery. |
| Project Title: | Lipid emulsion in resuscitation of ropivacaine cardiac toxicity in swine |
| Investigator(s): | Ng JKF, Leung GPH |
| Department: | Anaesthesiology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 09/2008 |
| Completion Date: | 02/2010 |
| Abstract: |
| Local anaesthetic agents are very useful drugs in anaesthesia for the performance of regional, local or topical anaesthesia. However, local anaesthetic agents can cause severe systemic toxicity, whihc usually manifest as cardiotoxicity and is frequently fatal. (1)(2)Systemic local anaesthetic toxicity is defintely the most severe complication that can occur under regional or local anaesthesia. Systemic toxicity may occur as a result of administration of an overdose of the local anaesthetic, or due to inadvertent intravascular injection. Previously there is no antidote for systemic local anaesthetic toxicity and the condition is frequently fatal. The use of lipid in resuscitation of local anaesthetic toxicity had gained much attention recently.(3)(4) Although the exact mechanism was not well defined, some enthusiastic authors suggested that it may become our first effective antidote to this most deadly regional anesthesia complication. (1) This hypothesis was first proposed by Weinberg, who has demonstrated a shift in the dose response curve to bupivacaine induced asystole in rats.(5)(6) He then further extend the test to life dogs. Lipid infusion was able to rescue dogs suffering from bupivacaine induced cardiac toxicity.(7) Different authors have very different opinions on the whether we should extrapolate the results to human.(8)(9) The clinical efficacy was first supported by a case report published 2006. Rosenblatt and colleagues successfully rescued a patient, who developed bupivacaine related cardiac arrest, with Intralipid after apparently failed resuscitation with advanced cardiac life support protocol. (10)(11) Current evidence therfore suggests that lipid infusion is effective in treating bupivacaine induced cardiac toxicity. However, all the above studies were conducted using bupivacaine. There is no study in the current literature to show the same beneficial effect of lipid in another commonly used long acting local anaesthetic agent, ropivacaine. Ropivacaine is a newer local anaesthetic agent which has claimed some benefit over bupivacaine in terms of e.g. differential motor and sensory block. We would like to find out if Intralipid is also useful in ropivacaine induced cardiovascular toxicity. The pharmacological properties of ropivacaine are very similar to bupivacaine. Their chemical structures resemble each other. They shared the same pKa and both have very high level of protein binding (95%). Ropivacaine is marketed as pure S-isomer. It has lower lipid solubility, intrinsic vasoconstricting property and stereo-specificity which distunguishes it from bupivacaine. (12) Ropivacaine at sufficiently high plasma concentration can also cause lethal cardiotoxicity. (13) While bupivacaine and ropivaciane are similar drugs, it has also been recently demonstrated that pre-treatment with clonidine, an alpha-2 adrenergic receptor agonist, may reduce the cardiac toxicity of ropivacaine, while ineffective for bupivacaine. (14) Of course pre-treatment is not very practical clinically as what is needed is an antidote that can be used after the development of toxicity. Nevertheless, the findings of this study suggests that ropivacaine and bupivacaine cardiotoxicity may have different mechanisms. Therefore although Intralipid has previously been shown to be effective in treating bupivacaine cardiotoxicity, its efficacy in cardiotoxicity induced by ropivacaine needs to be evaluated separately. The aim of our study is to investigate the efficacy of lipid emulsion in resuscitation of ropivacaine induced cardiac toxicity. In addition, all previous studies examining the efficacy of intralipid in bupivacaine induced cardiac arrest have not included a control group which has received effective cardiopulmonary resuscitation (CPR) according to current Advance Cardiac Life Support (ACLS) guidelines. In our study, the effect of intralipid will be compared to a control group which will receive active CPR according to current guidelines. Lastly, reduced myocardial mitochondrial ATP production has been shown to be one of the cellular mechanisms of bupivacaine cardiotoxicity. (15) The effect of Intralipid treatment on ropivacaine induced cardiotoxicity and its relation to myocardial ATP will also be examined in the present study. References 1. Greensmith JE, Murray WB. Complications of regional anesthesia. Curr Opin Anesthesiol. 2006; 19: 531-7 2. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979; 51: 285-7 3. Picard J. Lipid emulsion to treat overdose of local anaesthetic: gift of the glob. Anaesthesia 2006; 61: 107-9 4. Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2003; 28: 167-9 5. Weinberg GL, VadeBoncouer T, Ramaraju Gopal A, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998; 88:1071-5 6. Weinberg GL, Ripper R, Murphy P, Edelman LB, Hoffman W, Strichartz G, Feinstein DL. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med 2006; 31: 296–303 7. Weinberg GL, Richard R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198–202 8. Dalgleish D, Kathawaroo S. Lipid emulsion to treat bupivacaine toxicity. (Correspondence). Anaesthesia 2005; 60: 822. 9. Gray H. Role of intralipid in the management of local anaesthetic toxicity. (Correspondence). Anaesth Intensive Care 2006; 34: 518 10. Rosenblatt MA, Abel M, Fisher GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% Lipid Emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006; 105: 217–8 11. Weinberg G. Lipid infusion resuscitation for local anesthetic toxicity: Proof of clinical efficacy. Anesthesiology 2006; 105: 7-8 12. Langan G, McLure HA. Review of local anaesthetic agents. Curr Anaesth Crit Care. 15, 2004; 247-54 13. Groban L, Deal D D, Vernon J C. Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg 2001; 92: 37-43 14. Gulec S, Aydin Y, Uzuner K, Senturk Y. Effects of clonidine pre-treatment on bupivacaine and ropivacaine cardiotoxicity in rats. Eur J Anaesthesiol 2004; 21: 205-9. 15. DeLaCoussaye JE, Bassoul B, Albat B, et al. Experimental evidence in favor of role of intracellular actions of bupivacaine in myocardial depression. Anesth Analg 1992; 74: 698-702. |
| Project Title: | Effect of desmopressin on platelet dysfunction associated with mild hypothermia in healthy volunteers |
| Investigator(s): | Ng JKF, Cheung CW |
| Department: | Anaesthesiology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 12/2009 |
| Abstract: |
| Mild hypothermia (34-35℃) is known to cause platelet dysfunction[1,2]. Increased surgical bleeding and increased transfusion requirement at this temperature range has been reported in both cardiac and noncardiac surgeries[3-5]. This degree of hypothermia is common during any general anaesthesia. During general anaesthesia, patients suffer from both increased heat loss and reduced heat generation. Heat loss typically occur as a result of distribution of core heat to surface following vasodilatation which acoompanies the administration of most anaesthtic agents. Large area exposure, which is required during many surgical procedures, e.g. in burn patients, will significantly aggravate this. Heat loss also occur via the respiratory tract as a result of mechanical ventilation using dry gas, via exposure to cold intravenous fluids and blood products and via impairment of the body's natural heat conservating mechanisms such as piloerection during general anaesthesia. Heat production is reduced as a result of the decrease in metabolic rate and absence of muscular activity after induction of general anaesthesia[6]. Although this hypothermia-induced platelet dysfunction seems to be reversible with warming[7,8], warming is not always possible or desirable. During major trauma or burn surgery, surface warming of patient is practically difficult. During surgeries with major blood loss and fluid shift, heat loss usually occurs at a rate that is more rapid than any warming device can catch up with. Under such circumstances, adequate warming is frequently impossible and patients can bleed excessively in the presence of hypothermia-induced platelet dysfunction. Sometimes hypothermia is induced as a therapeutic procedure. This can happen during neurosurgery when cooling may be beneficial to neurological outcome[9]. Recently, it has also been shown that induced hypothermia is beneficial for patients who has been succesfully resuscitated from a cardiac arrest[10,11]. Under such circumstances, rewarming may be undesirable and hypothermia-induced platelet dysfunction may carry risks of bleeding related morbidity and mortality[12]. Desmopressin (DDAVP) is a drug which has proven efficacy in improving platelet function in uraemic and cirrhosis patients, and in reducing blood loss in selected surgeries[13]. In a recent in vitro study, we have found that desmopressin significantly improves platelet function at 32℃[14]. However, a number of questions remain unanswered. First, in our last study, desmopressin was added in vitro. One of the major mechinsms by which desmopressin improves haemostasis is via improvement of platelet-von Willebrand factor interaction[15]. This cannot be assessed in an in vitro model where endothelial cells are not present. Moreover in this study, the improvement is seen with a very low concentration of desmopressin in vitro, which suggests that probably doses much smaller than the "standard dose" (15 mcg slow iv or subcutaneous) may be useful. We have therefore designed this study as a follow up to our last study. 1. Wolberg A et al. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma 2004: 56: 1221-8. 2. Michelson A et al. The effects of aspirin and hypothermia on platelet function in vivo. Br J Haematol 1999; 104: 64-8. 3. Cavallini M et al. Effects of mild hypothermia on blood coagulation in patients undergoing elective plastic surgery. Plast Reconstr Surg 2005; 116: 316-21. 4. Hofer C et al. Influence of body core temperature on blood loss and transfusion requirements during off-pump coronary artery bypass grafting: A comparison of 3 warming systems. J Thorac Cardiovasc Surg 2005; 129: 838-43. 5. Schmied H et al. Mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty. Lancet 1996; 347: 289-92. 6. Sessler D. Temperature monitoring and perioperative thermoregulation. Anesthesiology 2008; 109: 318-38. 7. Winkler M et al. Aggressive warming reduces blood loss during hip arthroplasty. Anesth Analg 2000; 91: 978-84. 8. Schmied H et al. The effects of red-cell scavenging, hemodilution, and active warming on allogenic blood requirements in patients undergoing HIP or knee arthroplasty. Anesth Analg 1998; 86: 387-91. 9. Todd M et al. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005; 352: 135-45. 10. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549-56. 11. Bernard S et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346: 557-63. 12. Tam LK, Ng KFJ. The role of desmopressin in a patient with severe coagulopathy aggravated by mild therapeutic hypothermia [letter]. Resuscitation, in press. 13. Flordal P et al. Use of desmopressin to prevent bleeding in surgery. Eur J Surg 1998; 164: 5-11. 14. Ying CLA, Tsang SF, Ng KFJ. The potential use of desmopressin to correct hypothermia-induced impairment of primary haemostasis – An in-vitro study using PFA-100. Resuscitation 2008; 76: 129-33. 15. Mannucci P. Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 1988; 72: 1449-55. |
| Project Title: | Vascular effects of dexmedetomidine |
| Investigator(s): | Ng JKF, Leung GPH, Vanhoutte PMGR |
| Department: | Anaesthesiology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2010 |
| Abstract: |
| 1) To map out the detailed distribution of alpha2-adrenergic receptor subtypes (namely alpha2A/D, alpha2B and alpha2C) in porcine large coronary and coronary resistance arteries; 2) To study the effect of dexmedetomidine in relaxing/ contracting porcine large coronary and coronary resistance arteries; 3) To correlate the vascular effects of dexmedetomidine with the detailed distribution of alpha2-adrenergic receptor subtypes in porcine large coronary and coronary resistance arteries; 4) To study the effect of dexmedetomidine in relaxing/ contracting rat aorta and mesenteric artery under control and endotoxaemic conditions; 5) To study the mechanisms involved in the changes in vascular effects of dexmedetomidine in endotoxaemic rats. |
| List of Research Outputs |
| Liang C., Au A.L.S., Leung S.W.S., Ng J.K.F., Feletou M., Kwan Y.W., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-Derived Nitric Oxide Inhibits the Relaxation of the Porcine Coronary Artery to Natriuretic Peptides by Desensitizing Big Conductance Calcium-Activated Potassium Channels of Vascular Smooth Muscle, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334(1): 223-231. |
| Researcher : Qu C |
| List of Research Outputs |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Beneficial vascular effect of a non-selective PPAR activator in aorta of spontaneously hypertensive rats, Experimental Biology 2010, Anaheim, CA, USA. 2010. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Chronic Inhibition of Nitric-Oxide Synthase Potentiates Endothelium-Dependent Contractions in the Rat Aorta by Augmenting the Expression of Cyclooxygenase-2, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334,No.2: 373-380. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Differential Effects of PPAR Agonists on Vascular Reactivity in Aortas of Spontaneously Hypertensive Rats, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Researcher : Qu C |
| List of Research Outputs |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Beneficial vascular effect of a non-selective PPAR activator in aorta of spontaneously hypertensive rats, Experimental Biology 2010, Anaheim, CA, USA. 2010. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Chronic Inhibition of Nitric-Oxide Synthase Potentiates Endothelium-Dependent Contractions in the Rat Aorta by Augmenting the Expression of Cyclooxygenase-2, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334,No.2: 373-380. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Differential Effects of PPAR Agonists on Vascular Reactivity in Aortas of Spontaneously Hypertensive Rats, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Researcher : Shi Y |
| List of Research Outputs |
| Shi Y. and Vanhoutte P.M.G.R., Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes, Journal of Diabetes. 2009, 1: 151-162. |
| Researcher : Sit SM |
| List of Research Outputs |
| Ho Y.W., Sit S.M., Li R.W.S., Kwan Y.W. and Leung G.P.H., Involvement of Plasma Membrane Monoamine Transporter in Serotonin Uptake in Vascular Smooth Muscle Cells, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 67. |
| Researcher : So HL |
| List of Research Outputs |
| Chan K.H., Ho S.P., Yeung S.C., So H.L., Cho C.H., Koo M.W.L., Lam W.K., Ip M.S.M., Man R.Y.K. and Mak J.C.W., Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine. 2009, 103: 1746-1754. |
| Researcher : Tom WM |
| Project Title: | VII World Conference on Clinical Pharmacology and Therapeutics 4th Congress of the European Association for Clinical Pharmacology and Therapeutics Antidotal Mechanisms of Hydroxyacetone and Dihydroxyacetone in the Treatment of Acute Acetonitrile Poisoning |
| Investigator(s): | Tom WM |
| Department: | Pharmacology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 07/2000 |
| Abstract: |
| N/A |
| Researcher : Vanhoutte PMGR |
| Project Title: | Annual Summer School in Danish Cardiovascular Research Academy Veins in health and disease |
| Investigator(s): | Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 06/2007 |
| Abstract: |
| N/A |
| Project Title: | Endothelium-Derived Contracting Factor (EDCF) in spontaneous hypertension |
| Investigator(s): | Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2007 |
| Completion Date: | 08/2009 |
| Abstract: |
| (1) The proposed studies will pursue the long-term goal of the PI, to determine why hypertension alters the endothelial balance between the release of NO and that of EDCF. (2) The results should permit a better understanding of the events leading to endothelial dysfunction in hypertension and enable the design of novel therapeutic agents to correct the imbalanced release of endothelium-derived vasoactive substances. |
| Project Title: | Hypoxic contractions in coronary arteries |
| Investigator(s): | Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 09/2008 |
| Completion Date: | 08/2009 |
| Abstract: |
| Hypoxia causes a reduction in the production by endothelial NOS [eNOS] or in the bioavailability of endothelium-derived NO. When the latter is still present but reaches a critical level in the vascular smooth muscle cells, contraction ensues. The contraction is due either to the umasking of the effects of other endothelium-derived mediators or to a direct interaction of NO with the contractile process. |
| Project Title: | Causes of Dysfunction in Regenerated Endothelium |
| Investigator(s): | Vanhoutte PMGR, Tse HF |
| Department: | Pharmacology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 09/2008 |
| Abstract: |
| (1) To determine whether or not the changes (greater presence of A-FABP, increased oxidative stress, over-expression of tissue factor) predicted by earlier work in primary cultures derived from regenerated endothelial cells actually occur in freshly harvested segments of coronary arteries lined with regenerated cells; (2) If so, to determine whether or not chronic in vivo treatment can prevent the early endothelial dysfunction [selective loss of pertussis-sensitive activation of endothelial NO synthase (eNOS)] of regenerated endothelial cells following balloon denudation assessed in intact porcine coronary arteries studied ex vivo. In function of the results obtained in 1, four possibilities will be explored: a)Chronic inhibition of the actions of fatty-acid-binding protein aP2 (A-FABP) b)Chronic inhibition of the production of oxygen-derived free radicals (ROS) c)Chronic inhibition of the expression of tissue factor (TF) d)Chronic inhibition of H1-histamine receptors. |
| Project Title: | Visiting Research Professors Scheme 2009-10 |
| Investigator(s): | Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | Visiting Research Professors Scheme |
| Start Date: | 09/2009 |
| Abstract: |
| To support the appointment of Professor Hak-Kim Chan as Visiting Research Professor in the Department of Pharmacology and Pharmacy. |
| Project Title: | A Study of the Relative Significance of Nitric Oxide Synthase vs NADPH oxidase in Endothelial Senescence |
| Investigator(s): | Vanhoutte PMGR, Wang Y |
| Department: | Pharmacology |
| Source(s) of Funding: | Small Project Funding |
| Start Date: | 10/2009 |
| Abstract: |
| The endothelium consists of a monolayer of cells lining the interior surface of blood vessels. Under physiological conditions, the endothelial cells are quiescent and possess vital secretory, synthetic, metabolic and immunologic functions (1). Macrovascular endothelial cells (EC) rarely divide, with a turnover rate of approximately once every three years. Under conditions that cause endothelial injury and atherogenesis, such as hypertension, high cholesterol levels and turbulent blood flow at branch points in the arterial tree, replication of endothelial cells is increased in order to epair the damaged area. However, the regenerated endothelial cells usually reach replicative senescence after a finite number of cell replication (2). Endothelial senescence contributes to age-associated cardiovascular diseases, including atherosclerosis. Vascular endothelial cells with senescence-associated phenotypes have been detected in the atherosclerotic regions of human aorta and coronary arteries. Multiple balloon endothelial denudations in non-atheromatous arteries promote the accumulation of senescent cells in the arterial wall. The senescent endothelial cells are characterized by a set of functional and morphological changes, including diminished eNOS activity and NO production, impaired endothelium-dependent vasodilatation, reduced proliferative capacities, increased production of pro-inflammatory molecules, and the large flat “fried egg” appearance. The causes of endothelial senescence and its associated vasomotor abnormalities remain poorly understood. The progressive oxidative damage of macromolecules resulting from the continual exposure to oxidative stress has long been implicated in ageing and age-related pathologies. Aged blood vessels are characterized by reduced control of antioxidant enzymes and an increased flux of reactive oxygen species. Oxidative stress can induce or accelerate the development of replicative senescence (3). Human endothelial cells are more susceptible to oxidative stress than others such as fibroblasts, which may be due to the differences in the reactive oxygen species (ROSs) generation and antioxidant defense mechanisms. Oxidative stress occurs when the redox homeostasis within the cell is altered, such as an overproduction of ROS or a deficiency in antioxidant defense mechanisms. ROSs include both free radicals, which typically have an oxygen- or nitrogen-based unpaired electron, and other species, such as H2O2. Classic examples of free radicals are superoxide anion (O2-), hydroxyl radicals (OH?.) and nitric oxide (NO.) The intracellular sources for free radicals include, but are not limited to, normal products of mitochondrial respiration, NADPH oxidase (NOX), nitric oxide synthases (NOSs), cyclooxygenases, lipoxygenases, cytochrome P-450 monooxygenases and xanthine oxidase. The relative contribution of these sources of ROS and the role of individual species in the pathogenesis of vasculature diseases are not well established. In endothelial cells ROS emanate from three major enzyme systems: uncoupled NOSs, NOX and the mitochondrial respiratory chain (4). Furthermore, and principally in the cases of ROS generation by uncoupled NOSs and NOX, there is cross-signaling that enables ROSs from one system to activate secondary ROS production by the other. There currently exists a considerable debate as to whether uncoupled NOSs or NOX is the primary site of ROS production (5). There are three isoforms of NOSs: endothelial, eNOS, or type III; neuronal, nNOS or type I and inducible, iNOS or type II. The first two are constitutively activated while iNOS is the inducible form of NOS. The principal form of NOS in ECs is eNOS, with lesser amounts of the other two. In the fully coupled state, NOS produces nitric oxide (NO). In the absence of substrate (arginine) or co-factor (BH4), NOS becomes uncoupled and produces superoxide anions which can subsequently combine with NO to form peroxynitrite(OONO-). The NOX is a membrane-bound enzyme complex. It is made up of six subunits, including a Rho guanosine triphosphatase (GTPase), usually Rac1 or Rac2, and five "phox" units, gp91-PHOX, p22phox, p40phox, p47phox and p67phox. The prototype of gp91-PHOX is referred as Nox2. During recent years, several novel homologues of NOX have been cloned, designed as Nox1-5 and Duox1-2. Activation of NOXs leads to superoxide production which can lead to OONO- formation when it combines with NO from NOS. The NOXs family of enzymes is related to the classical neutrophil respiratory burst oxidase. The genetic deficiency of NOX leads to a condition known as chronic granulomatous disease which is characterized by increased susceptibility to infection and death in infancy. The subunits gp91phox and p22phox are membrane-bound. The GTPase Rac is necessary to recruit the two cytosolic subunits, p47phox and p67phox, for the assembly of active NOX complex. Although EC appear to express most of the components, the functional importance of these subunits is not completely understood. We have established a reliable primary culture model for evaluating endothelial function and senescence in vitro (6). Endothelial cells harvested from the left circumflex, left anterior descending artery and right coronary arteries of female pig hearts are cultured for up to four weeks, with the medium changed every 48 hours and cells passaged at a ratio of 1:3 once per week. Primary porcine endothelial cells (PPECs) have a limited life span in culture. After three to four passages, they show senescence and decreased NO production. Note that the reduced proliferative capacity, the functional deterioration as well as the morphological changes from “cobblestone-like” young endothelial cells to the enlarged and flattened senescent endothelial cells are extremely similar to those observed in regenerated endothelium, which has been proliferating in vivo for 4 weeks after balloon injury. Compared to the young (passage one) cells, the old (passage four) PPECs have significantly high levels of malondialdehyde (MDA), the lipid peroxidation products, suggesting an elevated ROS production. However, the mechanisms underlying the increased oxidative stress and ROSs are unknown. Thus far there have been no studies quantifying NOX and NOSs in senescent endothelial cells, especially studies of the relative abundance and intracellular localization changes of NOX to NOSs, and how it related to the occurrence of senescence. Therefore, this study aims to address the following questions: 1] Which of the two enzymes systems in endothelial cells, NOS vs NOX, is present in greater abundance and how does this impact on endothelial senescence? 2] Do the dysregulated functions of NOSs and NOXs participate in the endothelial senescence caused by drugs that can induce stent thrombosis (ST)? Can ST be prevented or modified by drugs that have direct actions on NOS and NOX to increase nitric oxide and reduce ROS production? |
| Project Title: | Experimental Biology 2010 Beneficial Vascular Effect of a Non-selective PPAR Activator in Aorta of Spontaneously Hypertensive Rats |
| Investigator(s): | Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 04/2010 |
| Completion Date: | 04/2010 |
| Abstract: |
| N/A |
| List of Research Outputs |
| Chan C.K.Y., Mak J.C.W., Man R.Y.K. and Vanhoutte P.M.G.R., Nitric Oxide Synthase and Soluble Guanylyl Cyclase Activation are Required for Hypoxic Endothelium-Dependent Contractions of the Porcine Coronary Artery, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(957.2). |
| Feletou M. and Vanhoutte P.M.G.R., EDHF: an upadate, Clinical Science. 2009, 117: 139-155. |
| Feletou M., Kohler R. and Vanhoutte P.M.G.R., Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets, Current Hypertension Reports. 2010, 12: 267-275. |
| Feletou M., Vanhoutte P.M.G.R. and Verbeuren T.J., The Thromboxane/Endoperoxide Receptor (TP): The Common Villain, J Cardiovasc Pharmacol. 2010, 55(4): 317-332. |
| Feletou M., Huang Y.U. and Vanhoutte P.M.G.R., Vasoconstrictor prostanoids, Pflugers Arch - Eur J Physiol. 2010, 459: 941-950. |
| Hui X., Li H., Zhou Z., Lam K.S.L., Xiao Y., Wu D., Ding K., Wang Y., Vanhoutte P.M.G.R. and Xu A., Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1, J Biol Chem. 2010, 285(14): 10273-80. |
| Hui X., Lam K.S.L., Wang Y., Xu A., Li H., Vanhoutte P.M.G.R. and Wu D., Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1., The Journal of Biological Chemistry. the United States, American Society for Biochemistry and Molecular Biology, 2010, 285: 10273. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T., Vanhoutte P.M.G.R., Liu T.C., Sweeney G. and Wang Y., Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity., Diabetes. 2010, 59: 872-82. |
| Lee M.Y.K., Vanhoutte P.M.G.R. and Xu A., Pharmacological Inhibition Of Adipocyte-Fatty Acid Binding Protein (A-FABP) Improves Endothelial Function In Male Apolipoprotein E-Knockout Mice, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 56. |
| Lee M.Y.K., Wang Y. and Vanhoutte P.M.G.R., Senescence of Cultured Porcine Coronary Arterial Endothelial Cells Is Associated with Accelerated Oxidative Stress and Activation of NFKB, Journal of Vascular Research. 2009, 47: 287-298. |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., Contractions of the SHR Aorta to High Doses of Epigallocatechin Gallate are Due to Vasoconstrictor Prostanoids, Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(960.2). |
| Li Z. and Vanhoutte P.M.G.R., High Concentration of Epigallocatechin Gallate Induces Contractions of the Rat Aorta due to Production of Reactive Oxygen Species, Activation of Cyclooxygenase, Production of Prostanoids and Stimulation of Thromboxane-prostanoid Receptor, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.13. |
| Li Z., Koo M.W.L., Man R.Y.K. and Vanhoutte P.M.G.R., High Concentrations Of Epigallocatechin Gallate Induce Contractions Of The Rat Aorta Due To Production Of Reactive Oxygen Species, Activation Of Cyclooxygenase, Production Of Prostanoids And Stimulation Of TP-Receptors, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 58. |
| Liang C., Au A.L.S., Leung S.W.S., Ng J.K.F., Feletou M., Kwan Y.W., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-Derived Nitric Oxide Inhibits the Relaxation of the Porcine Coronary Artery to Natriuretic Peptides by Desensitizing Big Conductance Calcium-Activated Potassium Channels of Vascular Smooth Muscle, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334(1): 223-231. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Endothelium-derived nitric oxide inhibits the relaxation to CNP in the porcine coronary artery, 13th Research Postgraduate Symposium, December 10-11, 2008. 2009. |
| Liang C., Leung S.W.S., Ng J.K.F., Man R.Y.K. and Vanhoutte P.M.G.R., Inhibition of the relaxation to CNY by endothelium-derived nitric oxide in the porcine coronary artery, Twelfth Annual Scientific Meeting of Institute of Cardiovascular Science and Medince, December 13-14, 2008, Hong Kong. 2009. |
| Liang C., Xu A. and Vanhoutte P.M.G.R., Toll-Like Receptor 4 Deficiency Attenuates Insulin Resistance And Endothelial Dysfunction Associated With Obesity And Diabetes In Mice, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 51. |
| Liang C., Xu A. and Vanhoutte P.M.G.R., Toll-like Receptor 4 Deficiency Attenuates Insulin Resistance and Endothelial Dysfunction Associated with Obesity and Diabetes in Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(571.5). |
| Liu H., Lei S., Luo T., Xia Z.Y., Liu Y., Leung G.P.H., Vanhoutte P.M.G.R., Irwin M.G. and Xia Z., Nitroglycerin Reduces TNF- Toxicity To Endothelial Cells but Compromises the Protective Effects of Propofol, FASEB Journal. 2010, 24: 959.9. |
| Liu T.C., Xu A., Lam K.S.L., Man R.Y.K., Vanhoutte P.M.G.R., Mak T.W., Law K.M., Tse H.F., Liang C. and Wang Y., Endothelial Dysfunctions Induced by Aging and Diet-induced Obesity is Attenuated in Lipocalin-2 Knockout Mice, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.16. |
| Liu T.C., Xu A., Man R.Y.K., Mak T.W., Law K.M., Liang C., Vanhoutte P.M.G.R. and Wang Y., Endothelium-dependent Contractions Induced by Aging and Diet-induced Obesity are Attenuated in Lipocalin-2 Deficient Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(570.3). |
| Liu Y., Lei S., Liu H., Mao X., Wong G.T.C., Vanhoutte P.M.G.R., Irwin M.G. and Xia Z., PKC β inhibitor ruboxistaurin prevents the increase of 15-F2tisoprostane in the myocardium and plasma in Type 1 diabetic rats, FASEB Journal . 2010, 24: 572.1. |
| Liu Y., Lei S., Liu H., Mao X., Wong G.T.C., Vanhoutte P.M.G.R. and Xia Z., Ruboxistaurin attenuates hypertriglyceridemia in diabetic rats:Comparison with the antioxidant N-acetylcysteine, FASEB Journal. 2010, 24: 572.5. |
| Michel T. and Vanhoutte P.M.G.R., Cellular signaling and NO production, Pflugers Archiv - European Journal of Physiology.. 2010, 459: 807-816. |
| Nilius B., Serban D.N., Vanhoutte P.M.G.R. and Robert F., Furchgott and his heritage: endothelial vasomotor control, European Journal of Physiology. 2010, 459: 785-786. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Beneficial vascular effect of a non-selective PPAR activator in aorta of spontaneously hypertensive rats, Experimental Biology 2010, Anaheim, CA, USA. 2010. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Chronic Inhibition of Nitric-Oxide Synthase Potentiates Endothelium-Dependent Contractions in the Rat Aorta by Augmenting the Expression of Cyclooxygenase-2, The Journal of Pharmacology and Experimental Therapeutics. 2010, 334,No.2: 373-380. |
| Qu C., Leung S.W.S., Vanhoutte P.M.G.R. and Man R.Y.K., Differential Effects of PPAR Agonists on Vascular Reactivity in Aortas of Spontaneously Hypertensive Rats, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Serban D.N., Nilius B. and Vanhoutte P.M.G.R., The Endothelial Saga: the past, the present, the future, Pflugers Archiv European Journal of Physiology. 2010, 459(6): 787-792. |
| Shi Y. and Vanhoutte P.M.G.R., Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes, Journal of Diabetes. 2009, 1: 151-162. |
| Tang E.V.A. .H.C. and Vanhoutte P.M.G.R., Endothelial dysfunction: a strategic target in the treatment of hypertension?, Pflugers Arch - Eur J Physiol. 2010, 459: 995-1004. |
| Vanhoutte P.M.G.R., Converting Enzyme Inhibitors and Endothelial Dysfunction, Sixth International Conference Biology, Chemistry, and Therapeutic Applications of Nitric Oxide, Kyoto, Japan, June 14-18, 2010. 22: S37. |
| Vanhoutte P.M.G.R., Endothelial dysfunction and coronary disease, Basic & Clinical Medicine. 2009, 2009, 29 supp: 1. |
| Vanhoutte P.M.G.R., My twenty years at IUPHAR, Pharmacology International. 2009, 72: 26-29. |
| Vanhoutte P.M.G.R., Nitric Oxide, the gatekeeper of endothelial function, Sixth International Conference Biology, Chemistry, and Therapeutic Applications of Nitric Oxide, Kyoto, Japan, June 14-18, 2010. 22: S5. |
| Wang Y., Huang Y., Lam K.S.L., Li Y., Wong W.T., Ye H., Lau C.W., Vanhoutte P.M.G.R. and Xu A., Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase, Cardiovascular Research. 2009, 82: 484-492. |
| Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Chronic Treatment Of Vitamin D Derivatives Reduce Endothelium-Dependent Contractions In The Aorta Of The Spontaneously Hypertensive Rat, Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009. Hong Kong. Journal of the Hong Kong College of Cardiology.. 2009, 17(2): 53. |
| Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Vitamin D Derivatives Reduce Endothelium-dependent contractions in the Isolated Spontaneously Hypertensive Rat Aorta., 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Xia Z., Luo T., Liu H., Wang F., Xia Z.Y., Irwin M.G. and Vanhoutte P.M.G.R., L-arginine enhances nitrative stress and exacerbates tumor necrosis factor-alpha toxicity to human endothelial cells in culture: prevention by propofol, Journal of Cardiovascular Pharmacology. 2010, 55(4): 358-67. |
| Xu C., Xu A., Vanhoutte P.M.G.R. and Wang Y., The Metabolic and Vascular Protective Activity of SIRT1: From the Fat Point of View, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.27. |
| Zu Y., Liu L.I.N.G., Lee M.Y.K., Xu C., Liang Y., Man R.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells, Circulation Research. 2010, 106: 1384-1393. |
| Zu Y., Liu L., Xu A., Lam K.S.L., Lee M.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells, 34th FEBS Congress, Czech Republic, July 2009. 2009. |
| Researcher : Wang Y |
| Project Title: | The potential role of lipocalin-2 as an inflammatory adipokine that links obesity with insulin resistance and metabolic disorders |
| Investigator(s): | Wang Y, Xu A |
| Department: | Genome Research Centre |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2008 |
| Completion Date: | 06/2010 |
| Abstract: |
| To use overexpression system to evaluate whether elevation of circulating lipocalin-2 levels can have any effects on systematic insulin sensitivity, inflammation and energy metabolism. As the proposed budget has been cut, we will remove the second part of the experiment on using the euglycemic-hyperinsulinemic clamp for evaluating individual tissue insulin sensitivities. Nevertheless, the overall goal of this part of work will not be affected as the other measurements on insulin sensitivity (GTT and ITT), metabolic parameters (lipid, insulin and glucose levels) as well as the inflammatory markers will still be carried on for this objective and can help to elucidate the systematic effects of lipocalin 2; to focus on evaluating whether lipocalin2 deficiency can prevent the development of insulin resistance using lipocalin 2 knockout mice challenged with high fat diet and genetic obesity (db/db background). On the other hand, we will remove the neutralization experiment using lipocalin-2 antibody in order to save the cost. Again, this revised plan will not affect the overall objectives as both knocking-down approaches will achieve similar effects; to agree with the reviewer 1's suggestion that AMPK experiment is not necessary. In addtion, since we will be focusing on inflammatory and insulin-signalling pathways, the metabolic pathway Oligo GEArray analysis will not be performed. In the mean time, the investigations on the target tissues, including liver, adipose tissue and skeletal muscle will continue to be carried on. This more focused experimental plan will help the smooth running of the project by fitting in with the current budget and will not sacrifice general project objectives. |
| Project Title: | Cross-talk between SIRT1 and insulin signaling pathways: Potential roles in regulating systemic insulin sensitivity and energy metabolism |
| Investigator(s): | Wang Y, Xu A |
| Department: | Genome Research Centre |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2008 |
| Completion Date: | 12/2009 |
| Abstract: |
| Sirtuins are a family of NAD+-dependent protein deacetylases that regulate cellular functions through deacetylation of a wide range of signaling molecules, transcription factors, histones and enzymes etc. Sir2 (silent information regulator 2), the first gene discovered in this family, was originally shown to be involved in transcriptional silencing at cell-mating type loci and telomeres in yeast, and suppression of recombination at yeast ribosomal DNA (rDNA), through deacetylation of the epsilon-amino groups of lysines in the amino-terminal domains of histones [1-3]. Yeast sirtuins (Sir1-4)-mediated silencing contribute to the fundamental cellular processes such as proper cell cycle progression, radiation resistance, and genomic stability etc [4]. After years of intense studies, it is now clear that sirtuins are phylogenetically conserved from bacteria to humans and regulate cell functions far beyond gene silencing. The anti-aging effects of Sir2 was firstly demonstrated by Kaeberlein et al, who showed that in S. cerevisiae, integration of extra copies of Sir2 extended lifespan up to 30% [5]. Similar effects of Sir2 were subsequently observed in Caenorhabditis elegans and Drosophila melanogaster [6-9]. Overexpression of Sir-2.1 increased lifespan up to 50% in C. elegans. In Drosophila, an extra copy of Sir2 gene extended lifespan in female and male by 29% and 18% respectively. Seven human homologues of sirtuins, SIRT1-7, have been characterized to share the catalytic domain with Sir2 [10-12]. Like other family members of sirtuins, SIRT1-3 and 5 show NAD+-dependent protein deacetylase activities, whereas SIRT4 and 6 have been found to possess mono-ADP-ribosyl transferase activities [13-17]. Recent research indicates that through modulating the acetylation and deacetylation of various target proteins, sirtuins can elicit their diversified functions in cell type-specific manners, which have pathophysiological implications in cancer, obesity, inflammation and neurodegenerative diseases. The requirement of NAD+ as a co-substrate suggests that sirtuins might act as sensors of cellular energy and redox states and could be regulated by the cellular metabolic status. Indeed, yeast Sir2 and the mammalian homologue SIRT1 can be upregulated by calorie restriction, which promote survival in organisms ranging from yeast to rodents and primates [18, 19]. Despite that the roles of SIRT1 in mammalian aging have not been fully characterized, mounting evidences suggest that SIRT1 could be an important regulator in systemic energy metabolism and metabolic syndrome, and that the anti-aging effects of SIRT1 might be related to its metabolic regulations. In mice, the beneficial metabolic profiles associated with calorie restrictions, including improved glucose tolerance (lower blood glucose and insulin levels), decreased LDL cholesterol and triacylglycerol and increased HDL cholesterol etc, are at least partially attributed to the elevated SIRT1 expression levels [18, 20]. Transgenic mice overexpressing SIRT1 are leaner, more metabolically active and glucose tolerant, and display decreased circulating levels of lipid, glucose and insulin [21]. SIRT1 knockout mice show lower blood glucose and increased glucose tolerance compared with the wild-type mice [22]. Resveratrol, a polyphenol found in red wine that contributes to the “French paradox”, a phenomenon of lower incidence of metabolic diseases despite their high saturated fat diet, might elicit its metabolic regulatory effects through activating SIRT1 [23-26]. The metabolic regulatory effects of SIRT1 on individual tissue have also been reported. SIRT1 inhibits adipogenesis in white adipose tissue by repressing activity of the proadipogenic nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ) [27]. SIRT1 enhances insulin secretions from pancreatic β cells by regulating UCP2 expressions [22, 28]. SIRT1 deacetylates and activates the transcriptional coactivator PGC-1α to increase gluconeogenesis in the liver [29, 30]. Notably, many of these metabolic functions of SIRT1 are observed under fasting status. Taken together, these results suggest that in mammalian system, SIRT1 possesses a broader range of metabolic regulatory functions in a tissue-specific manner, which might play important roles in maintaining energy homeostasis under different nutrient conditions and eventually executing a programme for extended lifespan. Despite these advances, the detailed signaling pathways and molecular mechanisms responsible for SIRT1-regulated cellular metabolism are far from clear. Sirt1 can regulate several transcription factors that govern metabolism, including PPARγ, PPARγ-coactivator 1α, and forkhead-box transcription factors (FOXOs), through direct interactions or modulating their acetylation/deacetylation status [31]. However, many of the metabolic effects mediated by SIRT1 could not be simply explained by activations of these transcription factors. The possible involvement of SIRT1 in insulin-signaling pathways has been suggested by the following evidences: Firstly, the insulin-IGF-I signaling pathway is nutrient activated, and decreased signaling through this pathway increases life span in C. elegans [32, 33]. and in mice [34]; Secondly, both calorie restriction and SIRT1 overexpression cause the reduced fat masses in mice, antagonizing the effects of insulin-induced fat storage and fat cell differentiation [27]; Thirdly, in the liver, overexpression of SIRT1 elicits catalytic activities, stimulates gluconeogenesis and fatty acid oxidation, and operates against the hepatic insulin response pathway, which stores glucose and represses gluconeogenesis [29, 35, 36]; Fourthly, SIRT1 and insulin possess opposing effects on the functions of PGC-1α and FOXO, two transcription factors involved in regulating metabolism and aging [37-40]; Furthermore, resveratrol, a well-known activator of SIRT1, inhibits the activity of PI3K and its downstream targets in human primary myotubes and muscle-derived cell lines, as well as in primary hepatocytes and liver-derived cell lines [41-43]. Collectively, these data suggest that SIRT1 might exert its metabolic functions through modulating insulin signaling activities. This project is thus designed to dissect the detailed cross-talks between SIRT1 and the insulin signaling pathways using both in vitro and in vivo approaches. The results are expected to shed important insights on the mechanisms that mediate the diversified metabolic functions of sirtuins. Specific objectives are: 1. To investigate whether overexpression of SIRT1 can antagonize insulin-evoked signaling pathways in several insulin-responsive cell lines (HepG2, C2C12 myocytes and 3T3-L1 adipocytes). 2. To evaluate whether or not SIRT1 physically interacts with the signaling molecules downstream of insulin receptor and modulate their acetylation/deacetylation status. 3. To elucidate whether adipose tissue-specific overexpression of SIRT1 could affect adiposity, systemic insulin sensitivity and energy metabolism in mice. |
| Project Title: | Molecular mechanisms underlying the hepato-protective functions of the fat cell-derived hormone adiponectin: potential roles of uncoupling protein 2 |
| Investigator(s): | Wang Y, Xu A |
| Department: | Biochemistry |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2009 |
| Abstract: |
| (1) To evaluate whether over-expression of UCP2 could alleviate the liver injuries associated with adiponectin deficiency and whether UCP2 ablation could abolish the hepatoprotective functions of adiponectin in mice: (2) To elucidate the detailed molecular and cellular mechanisms whereby UCP2 mediates the effects of adiponectin on inhibition of ROS production, inflammation and apoptosis in both primary hepatocytes and Kupffer cells; (3) To delineate the potential molecular and signaling pathways underlying the stimulatory effects of adiponectin on UCP2 expression. |
| Project Title: | Elucidation of the molecular mechanisms underlying endothelial aging using integrated proteomic profiling approaches |
| Investigator(s): | Wang Y, Vanhoutte PMGR |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2009 |
| Completion Date: | 09/2010 |
| Abstract: |
| Aging is a physiological process closely associated with the development of cardiovascular mobility and mortality independent of known cardiovascular risk factors1. Aging-related changes in the blood vessel include decreased antithrombogenic property of the endothelium, increased inflammation, impaired angiogenesis, reduced endothelium-dependent vasodilatations, as well as elevated expression of adhesion and proinflammatory/prothrombogenic molecules2. Endothelial cell senescence plays an important role in causing these aging-related vascular functional changes3. Cellular senescence originally referred to a limited ability of human cells to divide when cultured in vitro, a phenomenon accompanied by a specific set of phenotypic changes in morphology, gene expression and function4. It is now accepted that cellular senescence is a natural biological process. Its role in vivo is not unclear, and the specific molecular mechanisms underlying biological aging remain largely uncharacterized. Senescent endothelial cells cease to proliferate and do not respond to mitogenic stimuli. They lose their function and original morphology, but acquire a flattened cytoplasm (“fried egg” appearance), and can be frequently found on the surface of atherosclerotic plaque5. They show increased beta-galactosidase activity and impaired in vitro growth properties. The production of nitric oxide and eNOS activity are reduced in senescent human endothelial cells. Stimulation with proinflammatory cytokines exacerbates monocyte-endothelial cell interactions more profoundly in these cells. Thus, targeting endothelial cell senescence represents a promising therapeutic strategy for the treatment of atherosclerosis6. One popular explanation for senescence is the telomere hypothesis. Telomeres play a critical role in vascular cell senescence7-9. They are nonnucleosomal DNA-protein complexes at the end of chromosomes and serve as protective caps. During cell division, the extreme termini of chromosomes are not duplicated completely, which results in successive shortening of telomeres. The onset of senescence will be triggered by extremely short telomeres. The enzyme telomerase reverse transcriptase (TERT) and associated proteins are responsible for adding telomeres onto chromosome ends with its RNA moiety as a template. Both the validity of telomere length and the dynamic telomere components are critically involved in determining cell viabilities or aging10. Telomere homeostasis is regulated through multiple mechanisms, including protein composition, telomere length, and telomerase activity levels. In primary endothelial cell cultures, limited proliferative capacity correlates with telomere attrition and forced expression of human TERT results in extended cell life span or immortalization11. A direct correlation exists between TERT expression and neovascularization12. Endothelial cells from human abdominal aortae display age-dependent telomere shortening13. Correlations exist between short telomeres and hypertension, cardiovascular diseases, and myocardial infarction are consistently found 14. However, the detailed molecular mechanisms underlying telomere shortening and telomerase inactivation remain largely uncharacterized. Our laboratory has established a reliable primary cell culture model for evaluating endothelial function and senescence15. Endothelial cells are harvested from the coronary arteries of female pig hearts and cultured with the medium changed every 48 hours. Cells are detached with trypsin-EDTA and further passaged at a ratio of 1:3 at regular intervals (once per week) for 4 weeks. Primary porcine endothelial cells (PPECs) have a limited life span in culture. After four to five passages, they tend to de-differentiate and eventually reach senescence16. The cumulative population doubling is 19.18 from passage one to four, at which the cells show senescence and decreased NO production17. Microarray analysis revealed that their mRNA expression pattern resembles those observed in regenerated endothelium15, which has been proliferating in vivo for 4 weeks after balloon injury. The reduced proliferative capacity, the functional deterioration as well as the morphological changes from “cobblestone-like” young endothelial cells to the enlarged and flattened senescent endothelial cells are comparable between the two forms of senescence occurring in vivo and in vitro15, 17-20. More recent results demonstrate that the progressively decreasing telomerase activity is closely associated with the occurrence of senescence in PPECs (Figure 1), and that replenishment of an anti-aging protein SIRT1 restores the diminished telomerase activities (data not shown). Therefore, in order to further understand the underlying mechanisms of endothelial senescence, we plan to use proteomics-based approaches to systematically characterize the components of telomere complex and their dynamic changes during the aging process. The specific objectives include: 1. To purify and identify the components of telomerase complexes in normal and senescent PPECs using biochemical separations and Multidimensional Protein Identification Technology (MudPIT). 2. To characterize the detailed post-translational modifications occurring on TERT that may be associated with cellular senescence and contribute to the decreased telomerase activity. 3. To profile the differentially expressed nuclear proteins in PPECs undergoing senescence using isobaric tag peptide labeling mass spectrometry technology. |
| Project Title: | Discovery of novel inhibitors targeting lipocalin-2 for the treatment of obesity-related diabetes and cardiovascular diseases |
| Investigator(s): | Wang Y, Vanhoutte PMGR, Xu A |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Applied Research |
| Start Date: | 06/2010 |
| Abstract: |
| Type 2 Diabetes Mellitus (T2DM) and cardiovascular diseases (CVD) are two major causes of mortality and morbidity in the ageing population. Obesity is the most common risk factor for these inter-related metabolic and cardiovascular disorders. Chronic inflammation of the adipose tissue and dysregulated production of adipokines are the key mechanisms linking obesity to its associated pathologies (1, 2). The pro-inflammatory adipokines, such as leptin, resistin, retinol binding protein 4 and visfatin, act either in an autocrine manner to perpetuate local inflammation, or in an endocrine manner to induce systemic metabolic and vascular dysfunctions (3). Targeting these adipokines represents promising strategies for the treatment of obesity-associated medical complications. Several lipocalins produced in adipose tissue have been implicated in obesity-related metabolic syndrome and cardiovascular dysfunctions. For example, adipose tissue expression of retinoid binding protein-4 (RBP4) and the serum levels of this protein are elevated in insulin-resistant mice and in humans with obesity and T2DM, but normalized by the insulin-sensitizing drug rosiglitazone (4). Transgenic over-expression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance (5). Conversely, genetic deletion of RBP4 enhances insulin sensitivity. Another adipocyte-produced lipocalin, adipocyte fatty acid binding protein (A-FABP) also plays important roles in integrating systemic energy homeostasis, insulin sensitivity and inflammation (6). Targeted disruption of the A-FABP gene provides significant protection against both dietary and genetic obesity-associated insulin resistance, T2DM and fatty liver diseases, and also leads to marked alleviation of inflammation and atherosclerosis associated with ApoE deficient mice (6, 7). Orally active small-molecule inhibitor of AFABP is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models (8). Lipocalin-2, a 25-kDa secretory glycoprotein originally purified from human neutrophils, is highly expressed in adipose tissue (9-13). This protein structurally belongs to the lipocalin superfamily, with a characteristic cavity for binding small lipophilic substances (14). Recent studies from our laboratory and others have demonstrated a pivotal role of lipocalin-2 in the pathogenesis of obesity-related diabetes in both human and animal models (10-12). Lipocalin-2 expression in “inflamed” adipose tissue and plasma concentrations of this protein are markedly increased in obese/diabetic mice and humans, and that the augmented expression can be reversed by rosiglitazone, an insulin-sensitizing and anti-diabetic drug. Mice without lipocalin-2 are protected from ageing- and obesity-associated insulin resistance (15). Compared with their wild type littermates, obese lipocalin-2 knockout mice (Lcn2-KO) show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity. Overexpression of lipocalin-2 increases fasting glucose and insulin levels, and reduces insulin sensitivity in both wild type and Lcn2-KO mice. Obesity and diabetes are major risk factors for endothelial dysfunction, an early manifestation of vascular disorders (16). Under these conditions, endothelial cells can induce contractions of the underlying vascular smooth muscle by generating endothelium-dependent contracting factor (EDCF). EDCF can be enhanced by both high fat diet feeding and aging in mice. Our more recent work suggests that acetylcholine-induced EDCF-mediated responses are abolished in lipocalin-2 deficient mice. The contractions were inhibited by indomethacin (non-selective COX inhibitor), SC560 (COX-1 inhibitor) and S18886 (TP receptor antagonist), but not NS398 (COX-2 inhibitor), suggesting the involvement of COX-1. Lipocalin-2 treatment in cultures of endothelial cells promotes COX-1 expression trough a ROS-dependent mechanism. Additionally, in both aging and high fat diet conditions, LCN2-KO mice exhibit an increased aortic sensitivity to insulin-induced vasodilatation of aorta rings, which is accompanied by an enhanced insulin-stimulated eNOS phosphorylation. These evidence strongly support lipocalin-2 to be a causal factor in the development of insulin resistance, metabolic and vascular abnormalities. Hence, pharmacological agents that inhibit lipocalin-2 activity may offer therapeutic opportunities for obesity-associated metabolic, cardiovascular and inflammatory diseases. We have already filed a patent through HKU versitech to claim the use of lipocalin-2 as a therapeutic target to design the drugs for treatment of obesity and diabetes (US patent appl No: 20080095782). This application aims to collaborate with Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences to search for potent chemical inhibitors of lipocalin-2 as lead compounds, and to test their bioactivities in animal models. The data will be used to support the application for Guangdong-Hong Kong Technology Cooperation Funding Scheme (TCFS) of Innovation & Technology Funding (ITF) in the future. Specific objectives are: 1. Identification of the endogenous ligands binding to lipocalin-2 for structural-based drug design. 2. High-throughput screening of lipocalin-2 inhibitor compounds using fluorescence probe-based assays and affinity chromatography coupled to mass spectrometry analysis. 3. Cellular and animal-based assay for functional characterization and validation of lipocalin-2 inhibitors. |
| Project Title: | Lipocalin-2 and myocardial remodeling in response to ischemia-reperfusion injury |
| Investigator(s): | Wang Y, Vanhoutte PMGR, Xu A |
| Department: | Pharmacology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2010 |
| Abstract: |
| Obesity and the associated disorders [insulin resistance, hypertension, hyperlipidemia and type 2 diabetes mellitus (T2DM)] have a major impact on the incidence, severity, and outcome of ischemic heart disease (1). In the Framingham heart study, greater body mass index (BMI) is associated with an increased risk of heart failure in both men and women (2). The risk can be graded across categories of increasing BMI. Moreover, higher mortality rates as well as higher re-infarction and heart failure rates are found in diabetic patients, both during the acute phase and in extended postinfarction periods. While it is widely accepted that obesity increases the risk of developing heart disease, a number of reports also suggest a statistically significant survival benefit in obese patients with cardiovascular diseases (3). This phenomenon, referred as “obesity paradox”, has been described in patients with heart failure, particularly systolic heart failure (4), in cohorts with hypertension (5), coronary heart disease (6) and peripheral arterial disease (7). Importantly, evidence from clinical studies suggest that drugs for improving blood pressure and glucose metabolism may harm myocardial performance (8). Obesity is associated with structural changes in the heart. Pathologic cardiac remodeling, such as left ventricular (LV) hypertrophy, left atrial (LA) enlargement, and subclinical impairment of LV systolic and diastolic functions, are the precursors to overt cardiac dysfunction and heart failure (9). Increased cardiac mass has been postulated to result from increased epicardial fat and fatty infiltration of the myocardium (10). Increased accumulation of intramyocellular triglycerides and lipid metabolites in the heart has been found in the hearts of genetic obese animals, including ob/ob and db/db mice, Zucker rats, and those fed with high fat diet (9, 11, 12). Alterations in myocardial fatty acid metabolism and efficiency can cause decreased cardiac performance. Obese subjects, particularly those with insulin resistance, show increased myocardial fatty acid uptake and utilization (13), and subclinical contractile abnormalities (14). Animal studies using in vivo models, isolated perfused hearts, or in vitro cardiomyocyte cultures suggest that many of the changes in cardiac function are dependent on effects that may be secondary to obesity and altered glucose/lipid metabolism. Subtle changes in cardiac function can be observed in isolated hearts at time points when significant changes are not apparent when evaluated in vivo. For example, mildly impaired systolic function in vivo is absent in younger obese animals (<12 weeks of age), and become evident between 12 and 20 weeks of age, when evaluating by echocardiography. However, in isolated working hearts, significant reduction in cardiac power can be detected despite preserved in vivo cardiac function in animals before developing obesity and diabetes (15). Adipose tissue, once considered simply a lipid storage depot, is now known to function as a secretory organ producing a variety of bioactive molecules referred to as adipokines (16). Adipokines are believed to directly or indirectly affect the pathophysiology of various obesity-linked disorders and biological processes. Dysregulated adipokine production has been implicated in obesity-related cardiomyopathy. A number of these adipokines, such as leptin, adiponectin and apelin, elicit endocrine and paracrine effects on regulating cardiac functions (17, 18). For example, plasma adiponectin levels are inversely associated with the risk of myocardial infarction (19), and rapidly decline after acute myocardial infarction (20). Mice without adiponectin undergo worse myocardial ischemia-reperfusion injury than wide type control mice (21). Adiponectin mediates antihypertrophic effects in the heart in part through activation of AMPK signaling (22). Leptin concentrations are inversely correlated with LV mass, LV wall thickness, and left atrial size (23). Cross-sectional studies suggest a cardioprotective influence of leptin on LV remodeling. In fact, the temporal nature of changes in cardiac structure and function suggest that the “obesity paradox” phenomena may in part be explained by the dynamic actions of adipokines on the myocardium. Lipocalin-2 is an adipokine up-regulated in obese subjects (24). Its plasma levels are closely correlated with various metabolic and inflammatory parameters. Mice with deletion of the lipocalin-2 gene (Lcn2-KO) show improved systemic insulin sensitivity, decreased inflammatory cytokine production and attenuated inflammation in adipose tissue. Replenishment with lipocalin-2 in Lcn2-KO mice increases circulating blood glucose and insulin levels, and causes insulin resistance, suggesting that this adipokine is causally involved in the development of obesity-associated insulin resistance and metabolic abnormalities (25). There are a number of studies concerning the role of lipocalin-2 in the cardiovascular system. Its expression is significantly augmented in patients with coronary heart disease and independently associated with systolic arterial blood pressure, insulin resistance and HDL cholesterol (26). Lipocalin-2 levels are increased in atherosclerotic plaques and myocardial infarction (27). It may mediate the innate immune responses in the pathogenesis of heart failure (28-31). Recently, we have used the Langendorff-perfusion system to evaluate the heart functions of mice without lipocalin-2. Our results demonstrate that Lcn2-KO mice are protected from dietary obesity-induced impairment of heart functions (Figure 1). After 30 min of global ischemia and 60 min of reperfusion, Lcn2-KO mice show significantly improved recovery of LV contractility and decreased myocardial cell apoptosis compared to wide type mice (Figure 1, A and B). Moreover, histological analysis reveals that lipocalin-2 deficiency may modulate the myocardial structures (Figure 1C). These observations support a potential role of lipocalin-2 in the pathogenesis of obesity-related cardiac disorders. Therefore, this study aims to perform mechanistic analyses at cellular, molecular and systematic levels for understanding the pathophysiological roles of lipocalin-2 in myocardial remodeling in response to ischemia-reperfusion (I/R) injury in vivo. The specific objectives are: 1. To investigate whether the expression levels of lipocalin-2 are altered in the mice heart tissues undergoing myocardial I/R injury, and to analyze whether lipocalin-2 deficiency or replacement will affect the cardiac remodeling process in mice. 2. To examine whether lipocalin-2 deficiency affects the fat infiltration/ accumulation and the lipid profiles in the mice heart tissues, and to evaluate whether lipocalin-2 elicits direct effects on cardiomyocyte metabolism and function. 3. To identify possible mechanisms by which lipocalin-2 regulates cardiac remodeling, cardiomyocyte metabolism and function. |
| List of Research Outputs |
| Chow H.M., Sun R.W.Y., Lam J.B.B., Li C.K.L., Xu A., Abagyan R., Wang Y. and Che C.M., A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/b-catenin Pathway, Cancer Research. 2010, 70: 329-337. |
| Deng Y., Meyer U., Lam S.S.Y., Feldon J., Li Q., Wei R., Luk L., Chua S.E., Sham P.C., Wang Y. and McAlonan G.M., Prenatal immune challenge causes frontal-subcortical proteome changes relevant to schizophrenia and autism, The International Journal of Neuropsychopharmacol. 2010. |
| Hui X., Lam K.S.L., Wang Y., Xu A., Li H., Vanhoutte P.M.G.R. and Wu D., Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1., The Journal of Biological Chemistry. the United States, American Society for Biochemistry and Molecular Biology, 2010, 285: 10273. |
| Law K.M., Xu A., Lam K.S.L., Liu T.C., Berger T., Mak T.W., Zhang M.X.M. and Wang Y., Lipocalin 2-deficiency Attenuates Insulin Resistance Induced by High Fat Diet and Aging through Regulation of Lipid Metabolism and Inflammation in Adipose Tissue, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.06. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T., Vanhoutte P.M.G.R., Liu T.C., Sweeney G. and Wang Y., Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity., Diabetes. 2010, 59: 872-82. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T.W., Liu T.C., Sweeney G., Zhou M. and Wang Y., Mice Lacking Lipocalin-2 are Protected from Developing Insulin Resistance Associated with Aging and Obesity, 45th Annual Meeting of The European Association for the Study of Diabetes, September 29-October 2, 2009. Vienna - Austria. Diabetologia 2009. 52 supp:1: S20. |
| Lee M.Y.K., Wang Y. and Vanhoutte P.M.G.R., Senescence of Cultured Porcine Coronary Arterial Endothelial Cells Is Associated with Accelerated Oxidative Stress and Activation of NFKB, Journal of Vascular Research. 2009, 47: 287-298. |
| Leung T.Y., Wang Y. and Leung K.M.Y., Differential proteomic responses in adductor muscle and hepatopancreas of the green-lipped mussel Perna viridis to stresses induced by cadmium and hydrogen peroxide, the 6th international Conference on Marine Pollution and Ecotoxicology, 31 May-3 June 2010, City University of Hong Kong, Hong Kong. 2010. |
| Leung T.Y., Wang Y. and Leung K.M.Y., Differential proteomic responses in adductor muscle and hepatopancreas of the green-lipped mussel Perna viridis to stresses induced by cadmium and hydrogen peroxide, the SETAC Asia/Pacific 2010 Meeting, held during 4-7 June 2010 at Guangzhou, China. 2010. |
| Leung T.Y., Park T.J., Wang Y. and Leung K.M.Y., Proteomic profiling of metallothionein isoforms in the green-lipped mussel exposed to cadmium and hydrogen peroxide, The 3rd International Symposium of Integrative Zoology, July 7-10, 2009. Beijing, China . 2009. |
| Liu T.C., Xu A., Lam K.S.L., Man R.Y.K., Vanhoutte P.M.G.R., Mak T.W., Law K.M., Tse H.F., Liang C. and Wang Y., Endothelial Dysfunctions Induced by Aging and Diet-induced Obesity is Attenuated in Lipocalin-2 Knockout Mice, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.16. |
| Liu T.C., Xu A., Man R.Y.K., Mak T.W., Law K.M., Liang C., Vanhoutte P.M.G.R. and Wang Y., Endothelium-dependent Contractions Induced by Aging and Diet-induced Obesity are Attenuated in Lipocalin-2 Deficient Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(570.3). |
| Ngan E.S.W., Lau C.S.T., Wo Y.H., Chan W.K., Chan G.C.F., Wang Y., Kaplan D. and Tam P.K.H., Endocrine-gland vascular endothelial growth factor (EG-VEGF) in neuroblastoma tumor initiating cells, Advances in Neuroblastoma Research 2010, Stockham, Sweden, 21-24 June 2010. |
| Park T.J., Leung T.Y., Wang Y. and Leung K.M.Y., Cloning and characterization of a novel metallothionein gene in the green lipped mussel Perna viridis, the 6th international Conference on Marine Pollution and Ecotoxicology, 31 May-3 June 2010, City University of Hong Kong, Hong Kong. 2010. |
| Seneviratne C.J., Wang Y., Jin L.J., Abiko Y. and Samaranayake L.P., Proteomics of drug resistance in Candida glabrata biofilms, Proteomics 2010 Apr;10(7):1444-54., 2010. |
| Wang Y. and Xu A., Therapeutic potentials of adiponectin in fatty liver diseases. , The 21st IUBMB and 12th FAOBMB International Congress of Biochemistry and Molecular Biology. 2009. |
| Xu C., Xu A., Vanhoutte P.M.G.R. and Wang Y., The Metabolic and Vascular Protective Activity of SIRT1: From the Fat Point of View, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.27. |
| Zhou M., Xu A., Tam P.K.H., Lam K.S.L. and Wang Y., Adiponectin deficiency diminishes the anti-inflammatory activities of rosiglitazone in liver , The American Association for the Study of Liver Diseases. 2009. |
| Zhou M., Xu A., Tam P.K.H., Lam K.S.L., Chan L. and Wang Y., Cellular and Molecular Mechanisms Underlying the Hepatoprotective Functions of Adiponectin: Focus on Mitochondrial Functions and Uncoupling Protein 2, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.26. |
| Zu Y., Liu L.I.N.G., Lee M.Y.K., Xu C., Liang Y., Man R.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells, Circulation Research. 2010, 106: 1384-1393. |
| Zu Y., Liu L., Xu A., Lam K.S.L., Lee M.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells, 34th FEBS Congress, Czech Republic, July 2009. 2009. |
| Researcher : Wong SK |
| List of Research Outputs |
| Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Chronic Treatment Of Vitamin D Derivatives Reduce Endothelium-Dependent Contractions In The Aorta Of The Spontaneously Hypertensive Rat, Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009. Hong Kong. Journal of the Hong Kong College of Cardiology.. 2009, 17(2): 53. |
| Wong S.K., Man R.Y.K. and Vanhoutte P.M.G.R., Vitamin D Derivatives Reduce Endothelium-dependent contractions in the Isolated Spontaneously Hypertensive Rat Aorta., 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.22. |
| Researcher : Xia Z |
| Project Title: | Antioxidant attenuation of diabetic myocardial hypertrophy in diabetic cardiomyopathy: effects on myocardial PKC β2 overexpression |
| Investigator(s): | Xia Z, Irwin MG, Wong GTC, Wong TM |
| Department: | Anaesthesiology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 02/2008 |
| Completion Date: | 10/2009 |
| Abstract: |
| 1. To investigate the effects and mechanisms of NAC alone or in combination with Lithospermate B (LAB), an active component isolated from Salvia Miltiorrhizae known to have antioxidant properties, on the development of cardiac hypertrophy in diabetic rats; 2. To examine if the attenuation of cardiac hypertrophy produced by the PKC inhibitor LY333531 is mediated through the reduction of oxidative stress and enhancement of NO levels, and to explore the potential synergistic or addictive effects of PKC2 inhibition and antioxidant NAC or LAB on the development of cardiac hypertrophy and cardiomyopathy in diabetic rats; 3. To determine if PKCß2 activation is necessary for hyperglycemia-induced cardiomyocyte hypertrophy and the relationship between oxidative stress and PKCß2 activation. |
| Project Title: | Nitrate tolerance compromises propofol protection of the endothelium against inflammation: The role of PKC-beta2 and NADPH oxidase interaction |
| Investigator(s): | Xia Z |
| Department: | Anaesthesiology |
| Source(s) of Funding: | SCA Research Starter and MidCareer Grants |
| Start Date: | 07/2008 |
| Abstract: |
| (1) To determine the role of PKC- ß2 in the development of nitrate tolerance in human umbilical vein endothelial cells (HUVECs) and its relationship with NADPH oxidase activation, in the absence or presence of TNF- α stimulation. (2) To determine the effects of propofol on activation of PKC isoforms and NADPH oxidase subunits in HUVECs subjected to TNF- α stimulation, in the absence or presence of nitroglycerin or L-arginine supplementation. (3) To determine if treatment with propofol in combination with the selective PKC- ß2 inhibitor CGP53353 or NADPH oxidase inhibitor apocynin can prevent nitrate tolerance and attenuate TNF- α induced endothelial injury (in HUVECs) and dysfunction in isolated rat aortic rings. |
| Project Title: | L-Arginine Exacerbates TNF-Alpha Toxicity in Endothelial cells and Cardiomyocytes: Role of PKC-β2 activation |
| Investigator(s): | Xia Z, Irwin MG, Vanhoutte PMGR |
| Department: | Anaesthesiology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 05/2009 |
| Abstract: |
| HYPOTHESES: Supplementation of L-arginine will exacerbate pro-inflammatory cytokine tumor necrosis factor-α (TNF- α) induced vascular endothelial cell and cardiomyocyte injury. It does this by activating protein kinase C-ß (PKC- ß2) and NADPH oxidase. OBJECTIVES AND SPECIFIC AIMS: The purpose of the study is 1. to determine the role of PKC- ß2 in the development of nitrate tolerance in human umbilical vein endothelial cells (HUVECs) and its relationship with NADPH oxidase activation, in the absence or presence of TNF- α stimulation. 2. to determine the role of PKC- ß2 in TNF- α induced cardiomyocyte apoptosis, in the absence or presence of L-arginine supplementation. 3. to determine if treatment with antioxidant N-acetylcysteine (NAC) in combination with the selective PKC- ß2 inhibitor CGP53353 or NADPH oxidase inhibitor apocynin can prevent nitrate tolerance and attenuate TNF- α induced endothelial injury (in HUVECs) and cardiomyocyte injury. BACKGROUND and PRELIMINARY STUDY: Endothelium and myocardial ischemia-reperfusion injury (IRI): Coronary artery disease is a leading cause of death in many countries/regions. The morbidity and mortality attendant with myocardial ischemic injury/infarction remains significant despite advancement in surgical techniques and pharmacological therapies, in part due to the increased disease severity in the elderly or in patients with diabetes. Ischemia/reperfusion injury of the heart is not limited to cardiomyocytes but also extends to coronary vascular cells, and especially the coronary endothelium 1. Of interest, circulatory pro-apoptotic inflammatory cytokines (such as tumor necrosis factor [TNF]-α) and reactive oxygen species (ROS), which are increased during myocardial IRI and atherosclerosis, may promote cardiomyocyte apoptosis subsequent to the induction of endothelial cells apoptosis 2. Thus, inhibition of TNF- α and ROS induced endothelial cell apoptosis may represent an effective therapy for myocardial IRI. We observed that the antioxidant N-acetylcysteine (NAC) reduced TNF- α induced apoptosis in primary cultured human umbilical vein endothelial cells (HUVECs) 3and further increased nitric oxide (NO) content in the culture medium following TNF- α stimulation. To determine whether the increase in NO could favor endothelial cell survival under conditions of TNF- α stimulation, we supplemented the NO synthase (NOS) substrate L-arginine (100 μM, 30 min prior to the addition of TNF- α to cultured ECV304 cells (a cell line of HUVECs origin). The result was that L-arginine further increased TNF- α (24 hr stimulation) induced endothelial cell apoptosis with concomitant increases of NO production and superoxide production as well as increase of nitrotyrosine production (preliminary observation). We postulate that the development of nitrate tolerance is a mechanism responsible for these observed adverse effects of L-arginine. Nitrate tolerance and myocardial IRI: Nitrate tolerance (NT) is a phenomenon where the clinical or hemodynamic response to organic nitrates (such as nitroglycerin) is attenuated or abolished after prolonged, continuous, or high dose nitrate treatment 4. Increased PKC and NADPH oxidase activation, eNOS uncoupling and the subsequent increase in superoxide and peroxynitrite (ONOO-, product of superoxide and NO reaction) production in the vascular endothelium have been reported to play important roles in the development of NT 4-8, resulting in impaired endothelium-dependent vasodilatation . Most recent studies conducted in human and animal blood vessels reveal that oxidative inhibition of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2) 5; 9-12, plays an important role for the development of nitrate and cross-tolerance. Of note, NT has been shown to aggravate post-ischemic myocardial apoptosis and to impair myocardial functional recovery after ischemia in animal models 13, which can be reversed by treatment with glutathione 14, an endogenous “scavenger” of peroxynitrite. In an animal study, supplementation of L-arginine, a nitric oxide precursor, during late phase of myocardial ischemia/reperfusion (MI/R) increases myocyte apoptosis and exacerbates myocardial injury 15. In humans, supplementation of L-arginine has been shown to reduce NT following nitroglycerin treatment in patients with stable angina 16. However, large randomized clinical trial results indicate that L-arginine supplementation may be associated with higher postinfarction mortality following acute myocardial infarction (AMI) 17. Interestingly, a study published in February 2008 clearly shows that the expression of TNF- α converting enzyme at the site of ruptured plaques in patients with AMI is high, accompanied with increased systemic levels of TNF- α with patients with stable angina and these levels were significant independent predictors of adverse cardiac events in AMI patients 18. So, it seems plausible that L-arginine may have aggravated postinfarction mortality in patients with AMI 17 via enhancing TNF- α toxicity, or TNF- α facilitated the development of NT, leading to enhanced cardiac mortality. This notion is supported by our preliminary results that L-arginine exacerbated TNF-α toxicity in cultured human endothelial cells (data not shown). Potential role of PKC-β2 and NADPH oxidase in TNF-- α toxicity: Activation of PKC has been shown to play a critical role in TNF- α induced human endothelial cell apoptosis 19. We further demonstrated that PKC-β2 is the isoform that plays a dominate role in mediating TNF-α endothelial toxicity. The selective PKC-β2 inhibitor CGP53353 prevented TNF-α induced increase in endothelial cell apoptosis and the increase in cellular superoxide production (data not shown). Endothelial NADPH oxidase is a major source of superoxide in blood vessels and is implicated in the oxidative stress accompanying various vascular diseases 20-22. PKC-β activation has been shown to play important or critical roles in NADPH oxidase activation 23-25. PKC-β2 is preferably up regulated in failing human hearts 26-28 which is accompanied with increased levels of TNF- α production 18; 29 and NADPH oxidase activation 30-32. Therefore, PKC-β2 and NADPH oxidase interplay may play critical roles in mediating cellular damage in situations associated with increased TNF- α production, such as AMI, heart failure, diabetes as well as during cardiac surgery using cardiopulmonary bypass. TNF- α induces cardiomyocyte apoptosis and exacerbates heart failure. TNF- α has been shown to induce cardiomyocyte apoptosis 33-35, which is associated enhanced NADPH oxidase activation and oxidative stress. TNF- α also exacerbates heart failure 36. It is yet to be determined whether PKC-β2 activation contributes to TNF- α toxicity to the cardiomyocytes, and whether supplementation of L-arginine can aggregate TNF- α toxicity to the cardiomyocytes via PKC-β2 activation. |
| Project Title: | American Society of Anesthesiologists Annual Meeting 2009 Isoflurane and Propofol Synergy in Reducing Myocardial Ischemia−Reperfusion Injury in patients |
| Investigator(s): | Xia Z |
| Department: | Anaesthesiology |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 10/2009 |
| Completion Date: | 10/2009 |
| Abstract: |
| N/A |
| Project Title: | Synergy between N-acetylcysteine, allopurinol and/or PKC-beta inhibition attenuates diabetic cardiomyopathy in the rat |
| Investigator(s): | Xia Z, Irwin MG, Rong J, Vanhoutte PMGR, Wang Y |
| Department: | Anaesthesiology |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2010 |
| Abstract: |
| 1) To address the mechanisms underlying and the dose-response characteristics of the effect of NAC alone or in combination with allopurinol, an xanthine oxidase inhibitor, on the development of cardiac hypertrophy in diabetic rats; 2) To examine if PKC inhibition with LY333531 (ruboxistaurin) can attenuate cardiac hypertrophy through the reduction of oxidative stress and enhancement of the bioavailability of NO, and to determine the effects of alternating antioxidant treatment (with NAC and/or allopurinol) and PKC2 inhibition on the development of hypertrophic cardiomyopathy in diabetic rats; 3) To determine if PKCß2 activation is necessary for hyperglycemia-induced cardiomyocyte hypertrophy and the relationship between oxidative stress and PKCß2 activation. |
| Project Title: | PKC-beta2 Over Expression in the Myocardium of Diabetic Rats Compromises Opioid Agonist-Induced Cardioprotection |
| Investigator(s): | Xia Z, Irwin MG, Wong GTC |
| Department: | Anaesthesiology |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 03/2010 |
| Abstract: |
| Objectives: Objective 1. To determine the role of protein kinase C (PKC) beta 2 overexperssion and the subsequent NADPH oxidase activation in delta- and/or kappa-opioid agonist mediated acute cardioprotection hearts of diabetic rats. Objective 2. To confirm the role of NADPH oxidase in opioid preconditioning induced cardioprotection will be confirmed in hearts from NADPH oxidase subunit gp91phox gene knock-out mice (gp91phox-/) subjected to coronary ligation and reperfusion. Objective 3. To determine the relative role played by gp91phox and gp22phox in opioid induced cardiac protection. Myocardial ischemia-reperfusion injury and preconditioning Myocardial reperfusion is the restoration of blood flow to an ischemic heart, which is necessary to salvage the ischemic myocardium. However, reperfusion after a prolonged period of ischemia such as after myocardial infarction or in patients undergoing cardiac surgery using cardiopulmonary bypass results in oxidative stress and is a known causative factor of injury to cardiac muscle 1-4. Myocardial reperfusion injury is also seen after the use of primary percutaneous coronary intervention following myocardial infarction and this may account for significant morbidity 5; 6. Consequently the prevention of this has recently been suggested to be an important therapeutic target 6. Brief episodes of ischemia and reperfusion given before prolonged ischemia and reperfusion protect the myocardium and are termed ischemic preconditioning (IPC). However, numerous experimental studies reveal that the cardioprotective effects of these phenomena have been suppressed in the presence of some pathological factors such as hyperglycemia and obesity (see2 for a review). On the hand, although IPC is a powerful form of protection, its clinical application is limited because of ethical and practical reasons. Of interest, pharmacological preconditioning (PPC) with agents such as opioid agonists and adenosine, can also mediate cardioprotection via mechanisms similar to that of IPC. However, opioid agonist -induced preconditioning effect is also diminished in diabetic hearts7. Hearts of diabetic patients are less tolerant to ischemia. It is therefore important to develop strategies to restore diabetic heart sensitivity to preconditioning stimuli. Role of NADPH oxidase and protein kinase C (PKC) in preconditioning Recent studies show that NADPH oxidase activation plays a beneficial role in early ischemic preconditioning and that the activity of an upstream protein kinase C (PKC) isoform (such as PKC-delta or PKC-epsilon) is critical to preconditioning triggered NADPH oxidase activity and the subsequent cardioprotection8; 9. PKC-delta 10 and PKC-epsilon 11 activate NADPH oxidase through different mechanisms that involves the up-regulation of NOX1, a catalytic subunit of NADPH oxidase. Significance and possible outcome of proposed research We have shown that the opioid agonist remifentanil confers preconditioning-like cardioprotection via both cardiac kappa- and delta opioid receptors in rat hearts 12; 13 , and that the preconditioning effects of the opioid agonists rely on the activation of PKC 14; 15. However, remifentanil’s preconditioning effect is diminished in the hearts of diabetic rats. We also found that the myocardial NADPH oxidase protein is over expressed with a resulting increased enzyme activity, and that PKC-beta2 is also over expressed in the hearts of diabetic rats. Treatment with the antioxidant N-acetylcysteine normalized these changes 16. Of interest, N-acetylcysteine treatment also restores diabetic heart sensitivity to remifentanil preconditioning (please see preliminary data). Based on these findings, we hypothesize that: 1. Moderate NADPH oxidase activation subsequent to the and isoforms of PKC activation plays a critical role in preconditioning by opioid agonists and the resulting cardioprotection in the normal myocardium 2. In diabetes, NADPH oxidase over expression subsequent to persistent PKC-beta2 activation compromises or cancels opioid agonist-induced cardioprotection of the myocardium The testing of these hypotheses will provide insight into the mechanisms of why the heart of diabetics is less sensitive to pharmacological preconditioning. Most importantly, results gained from the proposed studies will facilitate the development of optimal therapeutic regimens in the prevention/treatment of myocardial ischemia-reperfusion injury in patients with diabetes. Overall outline of approach: We will firstly use general and isoform specific PKC inhibitors as well as a selective NADPH oxidase inhibitor to investigate the role of PKC and NADPH oxidase in opioid agonist preconditioning and cardioprotection in non-diabetic control rats (Sprague-Dawley) subjected to 30 min coronary artery ligation and 120 min reperfusion. Further, the role of NADPH oxidase in opioid preconditioning induced cardioprotection will be confirmed in isolated hearts [Langendorff model] from NADPH oxidase subunit gp91phox gene knock-out mice (gp91phox-/) subjected to global myocardial ischemia-reperfusion. Finally, the effects of opioid preconditioning induced protection on cultured cardiac myocytes subjected to simulated ischemia (120 min) and reperfusion (120 min) will be investigated in control cells as well as in myocytes transfected with gp91phox or gp22phox antisense, respectively, to look into the relative role played by gp91phox and gp22phox in opioid induced cardioprotection. |
| List of Research Outputs |
| Xia Z., Peer Reviewer, Biochemical Pharmacology 05/2010, 2010. |
| Xia Z., Peer Reviewer, European Journal of Pharmacology 03/2010, 2010. |
| Xia Z., peer reviewer, Canadian Journal of Anaesthesia . 2009. |
| Researcher : Xu A |
| Project Title: | The use of adiponectin as a biomarker to identify novel anti-diabetic and anti-atherogenic agents from Chinese herbs |
| Investigator(s): | Xu A, Qin GW, Lam KSL |
| Department: | Medicine |
| Source(s) of Funding: | NSFC/RGC Joint Research Scheme |
| Start Date: | 01/2006 |
| Abstract: |
| To determine and optimize the chemical structures for the three bioactive compounds isolated from Rhizoma Dioscoreae and Radix Astragali; to study the molecular mechanisms by which the three bioactive compounds induce adiponectin production from fat cells; to explore the therapeutic potentials of the three bioactive compounds in the treatment of T2DM, endothelial dysfunction, atherosclerosis and other obesity-related metabolic disorders in several well-established animal models. |
| Project Title: | Hypoxia inducible factor 1α as a mediator of obesity-induced chronic inflammation, aberrant production of adipokines, and insulin resistance |
| Investigator(s): | Xu A, Lam KSL, Chung SK |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2007 |
| Completion Date: | 12/2009 |
| Abstract: |
| To generate the transgenic mice with adipose tissue specific over-expression of the dominant negative form of HIF 1α to investigate the role of HIF 1α in obesity-induced macrophage infiltration and aberrant production of adipokines in adipose tissue, systemic inflammation and insulin resistance in the transgenic mouse models; to evaluate whether berberine, a compound with potent HIF 1α inhibitor activity, has therapeutic effects on obesity-associated chronic inflammation, insulin resistance and other metabolic abnormalities in mice. |
| Project Title: | Molecular mechanism underlaying the pathogenesis of type 2 diabetes |
| Investigator(s): | Xu A |
| Department: | Medicine |
| Source(s) of Funding: | Matching Fund for National Key Basic Research Development Scheme (973 Projects) |
| Start Date: | 05/2007 |
| Abstract: |
| To study molecular mechanism underlaying the pathogenesis of type 2 diabetes. |
| Project Title: | APPL1 as a novel modulator of endothelial nitric oxide production and endothelium-dependent vasodilation |
| Investigator(s): | Xu A, Chung SK, Wang Y |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2008 |
| Abstract: |
| To further define the role of APPL1 in the AMPK/eNOS signaling pathway, and to study the structural basis that underlies APPL1 actions; to characterize the phosphorylation sites of APPL1 and to investigate the role of phosphorylation in APPL1-mediated activation of AMPK/eNOS signaling cascade in endothelial cells; to test whether transgenic overexpression of APPL1 alleviates endothelial dysfunction associated with obese and diabetic mice. |
| Project Title: | Vascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention |
| Investigator(s): | Xu A, Lam KSL, Vanhoutte PMGR, Tse HF, Wong KB, Wang Y |
| Department: | Medicine |
| Source(s) of Funding: | Collaborative Research Fund (CRF) - Group Research Project |
| Start Date: | 06/2008 |
| Abstract: |
| To establish an integrated platform for in vivo and ex vivo evaluation of metabolic and vascular functions in transgenic rodent models; to examine in depth the roles of different oligomeric forms of adiponectin in preventing vascular diseases associated with obesity and diabetes, and to elucidate the receptor and postreceptor signaling pathways underlying the vasculo-protective properties of adiponectin; to investigate whether or not lipocalin-2 and A-FABP play an etiological role in the pathogenesis of vascular dysfunctions associated with obesity and diabetes, and to test the effects of the selective inhibitor of A-FABP in treating these diseases in mice; to evaluate the prospective and cross-sectional association of adiponectin, A-FABP and lipocalin-2, and their interactions, with the development of inflammation and vascular diseases in Chinese population. |
| Project Title: | Adipocyte fatty acid binding protein as a novel diagnostic marker and therapeutic target to combat vascular complications of diabetes: mechanisms and clinical implications |
| Investigator(s): | Xu A, Vanhoutte PMGR, Lam KSL |
| Department: | Medicine |
| Source(s) of Funding: | NSFC/RGC Joint Research Scheme |
| Start Date: | 01/2009 |
| Abstract: |
| To use A-FABP knockout mouse model to elucidate the pathological role of A-FABP in the development of endothelial dysfunction associated with diabetes; to investigate whether or not the selective chemical inhibitor of A-FABP can be used the treatment of vascular dysfunction in diabetic animal models; to study the detailed molecular mechanisms whereby A-FABP induces vascular inflammation and endothelial dysfunction; to conduct a joint clinical investigation to evaluate whether or not elevated serum A-FABP is causally associated. |
| Project Title: | Protective roles of AMP-activated protein kinase against vascular disease in diabetes: Molecular mechanisms and therapeutic intervention |
| Investigator(s): | Xu A, Vanhoutte PMGR |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2009 |
| Abstract: |
| (1) To use both in vivo and ex vivo approaches to study the physiological roles of AMPK in modulating the number and functionality of endothelial progenitor cells (EPCs), and to elucidate the molecular mechanism underlying AMPK actions in EPCs; (2) To investigate whether endothelium-specific activation of AMPK can alleviate diabetes-induced impairment in reendothelialization following carotid arterial injury; (3) To evaluate whether the selective activation of AMPK in endothelial cells is sufficient to reverse the impaired vasodilatation and augmented vasoconstriction in diabetic animal models. |
| Project Title: | Roles of APPL1 and APPL2 in insulin-mediated inhibition of hepatic glucose production: the serine/theonine kinase Akt as a common downstream target |
| Investigator(s): | Xu A, Xia F, Wang Y |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2009 |
| Completion Date: | 05/2010 |
| Abstract: |
| The liver is the primary organ responsible for endogenous glucose production, which is tightly controlled by various metabolic and nutritional factors. In the fasted state, hepatic glucose production is enhanced by glucagon to maintain euglycemia, thus ensuring that glucose-dependent tissues such as the brain have access to an energy supply. When blood glucose levels are elevated after nutrient ingestion, hepatic glucose production is suppressed by insulin. The inhibitory effect of insulin on hepatic glucose production is mediated by activation of Akt (also known as protein kinase B). Akt reduces the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) by suppressing the activity of FOXO1, a member of the forkhead family of transcription factors. In the absence of insulin, FOXO1 is localized in the nucleus where it transactivates the two gluconeogenic genes. Upon insulin stimulation, activated Akt phosphorylates FOXO1 at three conserved sites, inducing FOXO1 translocation to the cytoplasm and thereby reducing its transcriptional activity. In addition, activated Akt also inhibits the gluconeogenic program through a phosphorylation-dependent inhibition of the peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC-1α) and TORC2, both of which act in concert with FOXO1 in transactivating the gluconeogenic genes (Dentin et al., 2007; Li et al., 2007; Puigserver et al., 2003). Hepatic insulin resistance, which leads to excessive hepatic glucose production, is the major contributor to fasting hyperglycemia in patients with type 2 diabetes mellitus (T2DM) (Biddinger and Kahn, 2006; Magnusson et al., 1992). The central role of excessive hepatic glucose production in the pathogenesis of T2DM is underscored by the fact that current antidiabetic drugs such as metformin decrease blood glucose levels through inhibiting hepatic gluconeogenesis. Therefore, identification of novel molecules involved in regulating the hepatic insulin signaling pathway leading to the inhibition of glucose production might provide potential new targets for novel therapeutic intervention in the treatment of T2DM, a major health burden worldwide. APPL1, an adaptor protein containing an NH2-terminal Bin/Amphiphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain and a COOH-terminal phosphotyrosine binding (PTB) domain (Hosch et al., 2006), was originally identified as an interacting partner of Akt in a yeast two-hybrid assay using Akt2 as a bait (Mitsuuchi et al., 1999) (see Figure 1 in the attachment). Subsequent studies demonstrate that APPL1 binds to a number of cell surface receptors [TrkA(Lin et al., 2006; Varsano et al., 2006), DCC and adiponectin (Cheng et al., 2007; Mao et al., 2006), FSH) and intracellular signaling molecules (small GTPase Rab5(Miaczynska et al., 2004) and inositol 5-phosphatase(Erdmann et al., 2007), suggesting that APPL1 may act as a common relay to coordinate diverse signaling cascades. Notably, we have recently found that the interaction of APPL1 with adiponectin receptors is essential in mediating its insulin-sensitizing actions of adiponectin in muscle (Mao et al., 2006) and endothelial cells (Cheng et al., 2007). A more recent study on zebrafish demonstrates that APPL1 not only plays an essential role in Akt activation, but also determines Akt substrate specificity (Schenck et al., 2008). In mammalian cells, APPL1 has also been implicated in Akt activation by several extracellular stimuli including androgen and NGF-1 (Lin et al., 2006). Furthermore, APPL1 is required for insulin-stimulated translocation of GLUT4 from cytoplasm to plasma membrane and glucose uptake in adipocytes and myotubes (Saito et al., 2007). In primary rat hepatocytes, we showed that knockdown of APPL1 expression abolishes insulin-stimulated phosphorylation of Akt and its downstream targets, leading to impaired actions of insulin on inhibition of glucose production. Conversely, adenovirus-mediated APPL1 overexpression in liver reverses hyperglycemia, hyperinsulinemia and insulin resistance in db/db obese mice with frank diabetes. This data collectively suggests that APPL1 might be a physiological regulator of insulin sensitivity by activating the Akt signaling pathway. However, the molecular mechanisms whereby APPL1 potentiates insulin-evoked PI3K/Akt signaling remain elusive. APPL2 is cloned as a close homolog of APPL1. It shares 54% identity, 72% similarity and the same domain organization with APPL1 (See Figure-1 in the attachment). APPL2 forms a heterodimer with APPL1 through its BAR domain, and may play a similar role with APPL1 in mediating EGF-induced cell proliferation (Miaczynska et al., 2004) and cell survival(Schenck et al., 2008). By contrast, a recent study shows that some signaling molecules only bind to APPL1 but not APPL2, suggesting that these two adaptor proteins may possess distinct roles (Erdmann et al., 2007). The functions of APPL2 in regulating insulin sensitivity have never been explored so far. The primary objective of this study is to further define the role of APPL1 and APPL2 in modulating insulin sensitivity and hepatic glucose production, and to elucidate the detailed mechanisms involved in the actions of APPL1 and APPL2. Our specific objectives are: 1. To study in detail the structural basis and molecular pathways whereby APPL1 potentiates insulin-evoked Akt activation and inhibition of glucose production in rat primary hepatocytes. 2. To test our hypothesis that APPL1 activates Akt through competing with the endogenous inhibitor of Akt in primary hepatocytes, and to map the detailed domain of Akt involved in its interaction with APPL1. 3. To elucidate the role of APPL2, a close homolog of APPL1, in regulating hepatic insulin sensitivity and glucose metabolism in primary hepatocytes and various mouse models. Key references cited: Biddinger, S.B.et al (2006). Annu Rev Physiol 68, 123-158. Cheng, K.K., et al. (2007). Diabetes 56, 1387-1394. Dentin, R., et al. (2007). Nature 449, 366-369. Erdmann, K.S., et al. (2007). Dev Cell 13, 377-390. Hosch, S.E., et al (2006). Cell Metab 4, 5-6. Li, X., et al (2007). Nature 447, 1012-1016. Lin, D.C., et al (2006). Mol Cell Biol 25, 25. Magnusson, I.et al. J Clin Invest 90, 1323-1327. Mao, X., et al. (2006). Nat Cell Biol. 8, 516-523. Epub 2006 Apr 2016. Miaczynska, M. et al. (2004). Cell. 116, 445-456. Mitsuuchi, Y., et al (1999). Oncogene. 18, 4891-4898. Puigserver, P. et al. (2003). Nature 423, 550-555. Saito, T. et al. (2007). J Biol Chem 282, 32280-32287. Schenck, A., et al. (2008). Cell 133, 486-497. Varsano, T., et al. (2006). Mol Cell Biol 26, 8942-8952. |
| Project Title: | Characterization of Novel Adaptor Proteins Involved in Regulating Insulin Sensitivity and Glucose Homeostasis: from Molecular Mechanism to Physiological Implication |
| Investigator(s): | Xu A |
| Department: | Medicine |
| Source(s) of Funding: | General Research Fund (GRF) |
| Start Date: | 01/2010 |
| Abstract: |
| Refer to hard copy |
| Project Title: | Characterization of the receptor and postreceptor signaling events underlying the metabolic actions of FGF21, a potential therapeutic agent for treating obesity-related medical complications |
| Investigator(s): | Xu A, Hoo RLC, Wang Y |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2010 |
| Abstract: |
| With the rapid rise in the prevalence of overweight and obesity, diabetes has now reached an epidemic level and become a major public health threat worldwide. The latest report of the World Health Organization (WHO) suggested that over 250 million people are currently living with this disease. Without concerted actions to prevent diabetes, this figure will reach 380 million within a generation. In Hong Kong, the prevalence rate of diabetes exceeds 10% among adults, and is increasing rapidly in our ageing population. Diabetes is the primary risk factor for cardiovascular diseases (such as coronary artery disease and stroke), now the leading cause of death and disability among the elderly population. The current therapies for diabetes and its complications are suboptimal. Therefore, there is an urgent need to identify new therapeutic targets and to develop more effective therapies against diabetes and its complications. FGF21 is a secreted polypeptide with 210 amino acid residues that is expressed predominantly in the liver (Nishimura et al., 2000). It was first suggested as a metabolic regulator with potential antidiabetic properties during a high throughput screening for agents capable of increasing glucose uptake in 3T3-L1 adipocytes (Kharitonenkov et al., 2005). When administrated systemically to rodents and nonhuman primates with obesity and T2DM, recombinant FGF21 causes a variety of beneficial metabolic effects, including body weight loss, sustained decrease of plasma glucose and triglyceride to nearly normal levels, and also alleviation of insulin resistance (Kharitonenkov et al., 2005; Kharitonenkov et al., 2007). In rodent models with both dietary and genetic obesity, recombinant FGF21 has been shown to preserve beta-cell mass and functions (Wente et al., 2006), and to alleviate hepatosteatosis (Xu et al., 2009). Consistently, transgenic mice with overexpression of human or mouse FGF21 also exhibit significantly decreased levels of blood glucose, insulin, triglyceride and cholesterol, and improved insulin sensitivity and glucose clearance, as well as smaller adipocyte size compared to their wild type controls (Kharitonenkov and Shanafelt, 2008; Kharitonenkov et al., 2005) (Inagaki et al., 2007). Transgenic mice expressing human FGF21 were also resistant to high fat diet-induced weight gain and fat accumulation despite an increase in food intake (Kharitonenkov et al., 2005). The beneficial metabolic effects of FGF21 on hyperglycemia, hyperlipidemia and insulin resistance have also been observed in nonhuman primates with diabetes (Kharitonenkov et al., 2007). Noticeably, in nonhuman primates, recombinant FGF21 administration also leads to significant improvements in lipoprotein profiles, including lowering of low-density lipoprotein (LDL), cholesterol and raising low-density lipoprotein (HDL) cholesterol, and beneficial changes in the circulating levels of several cardiovascular risk markers (Kharitonenkov et al., 2007). Several unique biological properties of FGF21 make it an attractive drug candidate for the treatment of insulin resistance and diabetes. Firstly, although FGF21 structurally belongs to the FGF superfamily, both in vitro and in vivo experiments demonstrate that FGF21 does not possess mitogenic activities (Kharitonenkov and Shanafelt, 2008; Ryden, 2009). FGF21 transgenic mice do not develop neoplasia, tumor or any other overt abnormalities throughout their lifespan. In fact, transgenic mice with liver-specific overexpression of FGF21 display a markedly delayed process of tumor initiation in liver as measured by the frequency of diethylnitrosamine-induced adenomas and hepatocellular carcinoma (Huang et al., 2006). Secondly, despite its potent effects on decreasing hyperglycemia, FGF21 does not cause hypoglycemia events in any of the studies published so far (Kharitonenkov et al., 2005; Kharitonenkov et al., 2007). Thirdly, FGF21 does not induce weight gain and edema, which is a big caveat with many currently used anti-diabetic drugs.(Kharitonenkov and Shanafelt, 2008; Ryden, 2009). In addition to its insulin sensitizing and glucose-lowering activities, FGF21 has recently been found to play a key role in mediating the body’s adaptive responses to fasting and was proposed as a primary factor initiating the production of ketone bodies (ketogenesis) in the liver (Moore, 2007; Reitman, 2007). FGF21 expression in the liver is under the control of perioxisome proliferator-activated receptor (PPAR), a transcription factor that is activated during starvation (Badman et al., 2007; Inagaki et al., 2007). In rodents fed ketogenic diets, upon overnight fasting, or treated with the PPAR agonists, FGF21 mRNA expression in the liver is markedly elevated, but this effect is abrogated in PPAR-deficient diet. Elevated FGF21 causes adipose lipolysis, providing fatty acids to the liver for ketogenesis. FGF21 also induces torpor, a state characterized by physical inactivity and a low body temperature. Despite these promising findings, the receptor and postreceptor signaling events that underlie the metabolic actions of FGF21 remain poorly characterized. FGFs are known to mediate their actions via a set of FGF receptors that are expressed in multiple splice variants in (FGFR1-4). However, unlike classical FGFs that use heparin as a co-receptor, FGF21 does not possess heparin-binding properties (Ryden, 2009). In 3T3-L1 adipocytes, the metabolic actions of FGF21 have been shown to be dependent on β-klotho, a type I transmembrane protein that constitutively forms a complex with several members of FGFRs (Kharitonenkov and Shanafelt, 2008; Kurosu et al., 2007; Ogawa et al., 2007; Suzuki et al., 2008). FGF21 bind to the β-klotho- FGFR complexes through its NH2-terminus and COOH-terminus respectively, resulting in activation of the receptor complex. However, the specific subtypes of FGFRs involved and the downstream signaling pathways mediating the metabolic responses of FGF21 are yet to be established. Therefore, the current study is designed to identify the key targets of FGF21, and to investigate the molecular mechanisms underlying the metabolic actions of FGF21 in the liver. Our specific objectives are: 1. To investigate whether betaklotho is an essential receptor component mediating the hepatic actions of FGF21. 2. To determine the specific type of FGF receptors involved in the hepatic actions of FGF21. 3. To identify the proximal postrecptor signaling components involved in the hepatic actions of FGF21. 4. To elucidate the major metabolic pathways and target genes/proteins associated with acute or chronic FGF21 actions in the liver. |
| Project Title: | The 70th Scientific Sessions of American Diabetes Association Hypoxia Inducible Factor 1alpha Plays an Indispensible Role in the Thermogenic Functions of Brown Adipose Tissue in Mice |
| Investigator(s): | Xu A |
| Department: | Medicine |
| Source(s) of Funding: | URC/CRCG - Conference Grants for Teaching Staff |
| Start Date: | 06/2010 |
| Completion Date: | 06/2010 |
| Abstract: |
| N/A |
| Project Title: | Pharmacological inhibition of adipocyte fatty acid binding protein as a new strategy for treating obesity-related cardio-metabolic disorders |
| Investigator(s): | Xu A, Vanhoutte PMGR, Lam KSL |
| Department: | Medicine |
| Source(s) of Funding: | Seed Funding Programme for Applied Research |
| Start Date: | 06/2010 |
| Abstract: |
| Obesity and diabetes are known major risk factors for cardiovascular disease, including stroke, atherosclerotic heart disease, as well as diabetic nephropathy, neuropathy and retinopathy. Chronic inflammation, characterized by elevated concentrations of inflammatory biomarkers, is a “common soil” for these closely related diseases. In obese subjects, free fatty acids and a large number of pro-inflammatory factors released from adipose tissue can directly exert their actions on the vasculature to induce insulin resistance, endothelial dysfunction and inflammation, ultimately leading to diabetes and atherosclerosis. Therefore, pharmacological intervention with the inflammatory pathways that link adipose tissues and the vascular system represent an attractive therapeutic strategy for the treatment and/or prevention of obesity-related insulin resistance, type II diabetes as well as vascular disease. Adipocyte fatty acid binding protein (A-FABP), a 15 kDa lipid-binding protein predominantly expressed in adipose tissue, has been identified as a key pro-inflammatory mediator that links obesity with diabetes and its vascular complications (Hotamisligil and Erbay, 2008). Although traditionally recognized as an intracellular protein, we have recently identified a circulating form of A-FABP in the human bloodstream (Xu et al., 2006). We found that plasma levels of A-FABP are markedly elevated in obesity and correlate positively with insulin resistance, several classical cardio-metabolic risk factors and atherosclerosis (Tso et al., 2007; Xu et al., 2007; Yeung et al., 2008; Yeung et al., 2007; Yeung et al., 2009). A prospective study in our local Chinese community in Hong Kong has shown that serum A-FABP predicts the development of diabetes and metabolic syndrome, independently of sex, age, adiposity and other classical risk factors (Tso et al., 2007; Xu et al., 2007). Furthermore, a reduced risk for hypertriglyceridemia, type 2 diabetes and coronary artery disease was found in subjects who carry a functional genetic variant of the A-FABP gene that results in reduced A-FABP gene expression. Consistent with these clinical and genetic observations, the targeted disruption of the A-FABP gene in mice protects against obesity-induced dyslipidemia, hyperglycemia and insulin resistance, and results in a remarkable reduction (~88%) of atherosclerotic plaque formation in a rodent model with spontaneous development of atherosclerosis(Makowski et al., 2001). Double ablation of A-FABP and E-FABP (another minor form of FABP in adipose tissue) renders almost a complete protection against the development of metabolic syndrome in both dietary and genetic obesity(Maeda et al., 2005). Most importantly, an orally active pharmacological inhibitor of A-FABP appears to be effective for the treatment and prevention of diabetes and atherosclerosis in experimental animals ((Furuhashi et al., 2007). These clinical and animal studies suggest that A-FABP may represent a viable therapeutic target for the treatment and prevention of obesity-related medical complications, including type II diabetes and cardiovascular disease. Indeed, there are a number of advantages in using A-FABP as a therapeutic target: Firstly, since the expression of A-FABP is mainly restricted to adipose tissue (adipocytes and macrophages), the chemical inhibitors of A-FABP might be highly selective and do not have adverse effects; Secondly, because changes in A-FABP activity occurs at the very early stage of obesity, its chemical inhibitors can be potentially used for prevention of obesity-related diabetes and cardiovascular disease. As our research group has made significant contribution in discovery of circulating form of A-FABP and in confirming the clinical relevance of A-FABP in the pathogenesis of metabolic syndrome, diabetes and atherosclerosis in humans, we have recently signed a strategic alliance with the Servier Pharmaceuticals in France and we were granted with 450,000 Euro$ (~5 million HKD) to validate whether A-FABP is a viable therapeutic target in animal models. In collaboration with Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, we have identified three lead compounds using computer simulation technology. Our in vitro studies in macrophages found that two of the chemical compounds we have obtained are more potent in inhibition of lipid-induced inflammation than the commercially available compound BMS309403. The objective of this study is to establish an integrated platform for high throughput screening of A-FABP selective inhibitors and to test the therapeutic efficacy in animal models. The results obtained will be used to support the application of patents and external grants from ITF and other industrial sources. The specific objectives of this study are: 1) To establish a high throughput in vitro platform to test the specificity and bioactivity of A-FABP inhibitors; 2) To evaluate whether the three lead compounds are the selective inhibitors of A-FABP and to define the structural basis underlying the inhibitory effects of these compounds on lipid binding properties of A-FABP; 3) To investigate whether the lead compounds can alleviate obesity-related metabolic and vascular disorders in rodent models. (NOTE that Key references are listed in section VI). |
| List of Research Outputs |
| Cheung C.Y.Y., Tso A.W.K., Sham P.C., Xu A., Ong K.L., Cheung B.M.Y. and Lam K.S.L., Implication of the obesity-associated genetic variants identified from recent genome-wide association studies in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal.. 2010, 16: 15. |
| Chow H.M., Sun R.W.Y., Lam J.B.B., Li C.K.L., Xu A., Abagyan R., Wang Y. and Che C.M., A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/b-catenin Pathway, Cancer Research. 2010, 70: 329-337. |
| Law K.M., Xu A., Lam K.S.L., Liu T.C., Berger T., Mak T.W., Zhang M.X.M. and Wang Y., Lipocalin 2-deficiency Attenuates Insulin Resistance Induced by High Fat Diet and Aging through Regulation of Lipid Metabolism and Inflammation in Adipose Tissue, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.06. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T., Vanhoutte P.M.G.R., Liu T.C., Sweeney G. and Wang Y., Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity., Diabetes. 2010, 59: 872-82. |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T.W., Liu T.C., Sweeney G., Zhou M. and Wang Y., Mice Lacking Lipocalin-2 are Protected from Developing Insulin Resistance Associated with Aging and Obesity, 45th Annual Meeting of The European Association for the Study of Diabetes, September 29-October 2, 2009. Vienna - Austria. Diabetologia 2009. 52 supp:1: S20. |
| Lee M.Y.K., Vanhoutte P.M.G.R. and Xu A., Pharmacological Inhibition Of Adipocyte-Fatty Acid Binding Protein (A-FABP) Improves Endothelial Function In Male Apolipoprotein E-Knockout Mice, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 56. |
| Liang C., Xu A. and Vanhoutte P.M.G.R., Toll-Like Receptor 4 Deficiency Attenuates Insulin Resistance And Endothelial Dysfunction Associated With Obesity And Diabetes In Mice, Journal of the Hong Kong College of Cardiology, 2009/ Including Abstracts of Thirteenth Annual Scientific Meeting Institute of Cardiovascular Science and Medicine, The University of Hong Kong, December 12, 2009, Hong Kong.. 2009, 17(2): 51. |
| Liang C., Xu A. and Vanhoutte P.M.G.R., Toll-like Receptor 4 Deficiency Attenuates Insulin Resistance and Endothelial Dysfunction Associated with Obesity and Diabetes in Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(571.5). |
| Liu T.C., Xu A., Lam K.S.L., Man R.Y.K., Vanhoutte P.M.G.R., Mak T.W., Law K.M., Tse H.F., Liang C. and Wang Y., Endothelial Dysfunctions Induced by Aging and Diet-induced Obesity is Attenuated in Lipocalin-2 Knockout Mice, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.16. |
| Liu T.C., Xu A., Man R.Y.K., Mak T.W., Law K.M., Liang C., Vanhoutte P.M.G.R. and Wang Y., Endothelium-dependent Contractions Induced by Aging and Diet-induced Obesity are Attenuated in Lipocalin-2 Deficient Mice., Experimental Biology of Anaheim Convention Center, Anaheim, California, April 24-28, 2010. USA. The FASEB Journal. 2010, 24(570.3). |
| Wang Y. and Xu A., Therapeutic potentials of adiponectin in fatty liver diseases. , The 21st IUBMB and 12th FAOBMB International Congress of Biochemistry and Molecular Biology. 2009. |
| Xu C., Xu A., Vanhoutte P.M.G.R. and Wang Y., The Metabolic and Vascular Protective Activity of SIRT1: From the Fat Point of View, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.27. |
| Zhou M., Xu A., Tam P.K.H., Lam K.S.L. and Wang Y., Adiponectin deficiency diminishes the anti-inflammatory activities of rosiglitazone in liver , The American Association for the Study of Liver Diseases. 2009. |
| Zhou M., Xu A., Tam P.K.H., Lam K.S.L., Chan L. and Wang Y., Cellular and Molecular Mechanisms Underlying the Hepatoprotective Functions of Adiponectin: Focus on Mitochondrial Functions and Uncoupling Protein 2, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.26. |
| Researcher : Xu C |
| List of Research Outputs |
| Xu C., Xu A., Vanhoutte P.M.G.R. and Wang Y., The Metabolic and Vascular Protective Activity of SIRT1: From the Fat Point of View, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.27. |
| Zu Y., Liu L.I.N.G., Lee M.Y.K., Xu C., Liang Y., Man R.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells, Circulation Research. 2010, 106: 1384-1393. |
| Researcher : Yang C |
| List of Research Outputs |
| Yang C. and Leung G.P.H., 14, 15-epoxyeicosatrienoic Acid Induces Vasorelaxation Throuhg the Prostaglandin EP2 Receptors in Rat Mesenteric Artery, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.23. |
| Researcher : Zhou M |
| List of Research Outputs |
| Law K.M., Xu A., Lam K.S.L., Berger T., Mak T.W., Liu T.C., Sweeney G., Zhou M. and Wang Y., Mice Lacking Lipocalin-2 are Protected from Developing Insulin Resistance Associated with Aging and Obesity, 45th Annual Meeting of The European Association for the Study of Diabetes, September 29-October 2, 2009. Vienna - Austria. Diabetologia 2009. 52 supp:1: S20. |
| Zhou M., Xu A., Tam P.K.H., Lam K.S.L. and Wang Y., Adiponectin deficiency diminishes the anti-inflammatory activities of rosiglitazone in liver , The American Association for the Study of Liver Diseases. 2009. |
| Zhou M., Xu A., Tam P.K.H., Lam K.S.L., Chan L. and Wang Y., Cellular and Molecular Mechanisms Underlying the Hepatoprotective Functions of Adiponectin: Focus on Mitochondrial Functions and Uncoupling Protein 2, 14th Research Postgraduate Symposium of The University of Hong Kong Li Ka Shing Faculty of medicine, December 2-3, 2009. Hong Kong.. 2009, 1.26. |
| Researcher : Zu Y |
| List of Research Outputs |
| Zu Y., Liu L.I.N.G., Lee M.Y.K., Xu C., Liang Y., Man R.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 Promotes Proliferation and Prevents Senescence Through Targeting LKB1 in Primary Porcine Aortic Endothelial Cells, Circulation Research. 2010, 106: 1384-1393. |
| Zu Y., Liu L., Xu A., Lam K.S.L., Lee M.Y.K., Vanhoutte P.M.G.R. and Wang Y., SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells, 34th FEBS Congress, Czech Republic, July 2009. 2009. |