Obesity-related metabolic syndrome is major risk factor for cardiovascular diseases. Adiponectin (APN), a circulating fat-secreted cytokine, is implicated in protecting against obesity-related metabolic and cardiovascular dysfunctions. Levels of APN decrease with the expansion of adipose tissue and low levels are associated with coronary artery disease, hypertension, heart infarct and other cardiovascular dysfunctions. In animal models of cardiac hypertrophy and ischemic heart disease, administration of APN improves pathological myocardial remodeling. While the beneficial functions of APN are well described, little is known about membrane receptors that enable APN's physiological functions in the cardiovascular system. T-cadherin, an APN binding protein implicated by genetic linkage analysis in cardiovascular functions, is a candidate cell surface glycoprotein to mediate APN functions. This R21 application will explore the functions of T-cadherin in a mouse model of heart disease and relate a potential role to the functions of adiponectin.
Obesity contributes to metabolic and cardiovascular disorders by altering the levels of adipocyte-secreted pro- and anti-inflammatory cytokines in the circulation. Adiponectin is a fat-secreted anti-inflammatory cytokine with beneficial actions in regulating metabolic and cardiovascular functions. Adiponectin associates with cardiomyocyte and endothelial cell surfaces to exert beneficial functions. The receptors that enable the engagement of adiponectin with cell surfaces and lead to activation of downstream signaling cascades remain poorly understood. Research proposed in this application will explore the contributions of T- cadherin, a novel adiponectin-binding cell surface glycoprotein, in functions of the heart and vasculature. Specifically, the proposed experiments will test if T-cadherin is essential for the cardioprotective actions of adiponectin. This work will contribute to understanding adiponectin's cardiovascular-protective functions and - if successful - form a new basis for exploring the T-cadherin-adiponectin interaction as a possible drug target for recovery from cardiovascular injury.
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