GENOME RESEARCH CENTRE
| Researcher : Curtain RP |
| List of Research Outputs |
| Tang J., Feng Y., Tsao G.S.W., Wang N., Curtain R.P. and Wang Y., Berberine and Coptidis Rhizoma as novel antineoplastic agents: A review of traditional use and biomedical investigations. , Journal of Ethnopharmacology. . 2009, 126: 5-17. |
| Researcher : Fong PY |
| List of Research Outputs |
| So H.C., Fong P.Y., Chen R.Y.L., Hui T.C.K., Ng M.Y.M., Cherny S.S., Mak W.W., Cheung E.F.C., Chan R.C.K., Chen E.Y.H., Li T. and Sham P.C., Identification of Neuroglycan C and Interacting Partners as Potential Susceptibility Genes for Schizophrenia in a Southern Chinese Population, American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2010, 153B (1): 103-113. |
| Researcher : Leung TY |
| List of Research Outputs |
| Ng W.C., Leung T.Y. and Williams G.A., Comparative proteomic responses in two intertidal limpets (Cellana grata and Cellana toreuma) to summer low tides on tropical rocky shores, 3rd International Symposium of Integrative Zoology. July 7-10, 2009. Beijing, China. 2009. |
| Researcher : Mak WW |
| List of Research Outputs |
| So H.C., Fong P.Y., Chen R.Y.L., Hui T.C.K., Ng M.Y.M., Cherny S.S., Mak W.W., Cheung E.F.C., Chan R.C.K., Chen E.Y.H., Li T. and Sham P.C., Identification of Neuroglycan C and Interacting Partners as Potential Susceptibility Genes for Schizophrenia in a Southern Chinese Population, American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2010, 153B (1): 103-113. |
| 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 |
| 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. |
| Seneviratne C.J., Wang Y., Jin L.J., Abiko Y., Watamoto T. and Samaranayake L.P., Shotgun proteomics elucidates the regulatory pathway of Candida biofilms, Journal of Dental Research. 2009, 88 (Spec Iss B): 254 (PAPF/APR). |