Aging vasculopathy is the most common cause of morbidity and mortality in the United States. Substantial evidence suggests that environmental and genetic factors including diabetes, hyperlipidemia, and smoking act coordinately to precipitate clinically evident cardiovascular decline. Glucose-derived Advanced Glycation Endproducts {AGE} accumulate in vascular tissues of older persons many of whom, in addition, are diabetic. AGEs mediate a spectrum of cellular responses leading to multiple organ damage. This has been best exemplified in studies in which the administration of AGEs to normal animals produced widespread vascular dysfunction, atherogenesis, and enhanced stroke-induced brain damage. Among other cell types, endothelial cells {EC} express a cell-surface AGE-binding and internalizing receptor system which modulates EC function, inducing production of cytokines, adhesion molecules and thrombogenic mediators, and consequently influencing vascular structure/function in ways that predisposes this system to age-related damage. In susceptible individuals, altered EC AGE receptor expression and function, together with metabolic or environmentally-induced abnormalities, may synergize over decades to compromise the balance of critical gene regulatory functions within the vascular system. The goals of this continuation proposal are to elucidate: 1a: human EC AGE receptor cell biology, the intermolecular relationships, receptor assembly, and requirements for each receptor component to effect ligand binding and processing; 1b: human EC AGE receptor contribution to and requirement for cell activation, evidenced by changes in membrane phosphatidylinositol, diacylglycerol, calcium, protein kinase C and protein phosphorylation, 2: human EC AGE receptor mRNA, protein and functional regulation by known risk factors associated with vasculopathy, including glucose, insulin, AGE-modified proteins, AGE-LDL and oxidized-LDL, as well as of endogenous AGEs {present in serum of diabetic patients, chronic smokers, or after exposure to AGE-rich diet}; 3a: in vivo AGE receptor regulation by known risk factors: aging, hyperlipidemia, chronic smoking and an AGE-rich diet, utilizing various animal models, and 3b: correlation of vascular disease severity, AGE levels and AGE receptor expression in human aortic autopsy specimens from young and older humans with or without vascular disease. Based on the multifaceted properties of the AGE receptor system, these studies should provide a molecular basis for the future epidemiology and treatment of age-related vascular disease.
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