(Taken directly from the application): Atherosclerotic vascular disease is the leading cause of death among persons with diabetes mellitus. Compared with the general population, diabetic men are two-to four-times more likely to develop macrovascular disease, and the risk is three- to six-fold greater than normal for diabetic women, who lose the usual premenopausal protection. Because elevated blood glucose is the hallmark of diabetes and because glucose has been implicated in diabetic vascular damage, this project will focus on glucose as a possible facilitator of plaque development. Multiple lines of evidence implicate oxidized low density lipoprotein (LDL) as an important atherogenic agent. Moreover, glucose itself causes LDL oxidation in vitro, indicating that glucose may directly stimulate oxidation reactions. Alternatively, glucose might promote LDL oxidation indirectly, by activating the production of oxidants by cells of the arterial wall. The overall goal of this proposal is to test the hypothesis that elevated glucose levels in diabetic patients promote atherosclerosis by enhancing the conversion of LDL to a known atherogen, oxidized LDL. We will explore three pathways that promote LDL oxidation in vitro: glycoxidation, myeloperoxidase and reactive nitrogen intermediates. We will seek evidence for the operation of these pathways through complementary studies analyzing human aortic tissue, mouse models and cultured cells. By combining in vitro studies with the analysis of human and mouse atherosclerotic tissue, we ultimately hope to identify the specific biochemical pathways for LDL oxidation that are triggered by hyperglycemia, with important implications for the pathogenesis of diabetic macrovascular disease.
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