Our overall goal to understand the role of the adipokine adiponectin in vascular function, atherosclerosis, and coronary heart disease. Adiponectin is produced exclusively by adipocytes and is found at high levels in the intima surrounding several types of blood vessels. Adiponectin plays a key role in regulating hepatic and muscle fat and glucose metabolism and also the metabolism and proliferation of vascular smooth muscle and possibly endothelial cells. We identified several adiponectin orthologs, expressed mainly by adipocytes that share biological activities and signaling properties with adiponectin;these, like adiponectin, may regulate metabolism of vascular cells. The identities of the adiponectin signaling receptors and signal transduction pathways are not known;our and other labs have unequivocally shown that previously reported, putative signaling receptors for adiponectin do not function in that capacity. We identified T-cadherin, a GPI- anchored surface protein, as an adiponectin binding protein that is highly and specifically expressed by cells in the blood vessel intima. Deletion of T-cadherin in mice results in a decrease in adiponectin in the vasculature and a major increase in the circulation, indicating it is a major adiponectin receptor. However, additional cell surface receptors are necessary to mediate adiponectin signaling. We will clone these signaling adiponectin receptors, analyze their structures and functions in vitro and in vivo, and determine the signal transduction pathways activated in cultured vascular endothelial and smooth muscle cells by the three isoforms of adiponectin, focusing initially on the AMP- activated protein kinase, and NF-kB, MAP kinase, and NO pathways. Cells from T-cadherin -/- mice will allow us to continue to explore the role of this receptor in adiponectin signaling and localization in the vasculature. Importantly, with Projects I and II we will determine the effects of the various isoforms and orthologs of adiponectin and of T-cadherin on blood vessel endothelial and smooth muscle cells and on atherosclerosis and CHD in apoE -/- and SR-BI/apoE double knockout (dKO) mice. Thus, over the coming five years we hope to elucidate the roles of adiponectin and its principal vascular binding protein, T-cadherin, in maintaining the normal state of vascular endothelial and smooth muscle cells, and understand whether and how deletion of either of these proteins leads to atherosclerosis, thrombosis and CHD.
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