The excessive cardiovascular mortality associated with diabetes mellitus represents a severe and unacceptable burden for afflicted individuals both nationally and worldwide. The reasons underlying the excess cardiovascular mortality in diabetes include: 1) accelerated atherosclerosis; 2) ventricular contractile dysfunction resulting from metabolic abnormalities in cardiac myocytes; and 3) an increased susceptibility of diabetic myocardium to acute ischemia. The magnitude of these diverse myocardial and vascular sequelae of diabetes are directly related to the severity and duration of hyperglycemia itself suggesting a direct relationship of alterations in glucose metabolism to these end-organ effects. Recently, our laboratory has identified a novel metabolic paradigm in which glycolytic flux is coupled to the generation of lipid second messengers by regulating the activity of a calcium- independent phospholipase A2 catalytic complex. Accordingly, the unifying hypothesis embodying this program project is that the vascular and myocardial sequelae of diabetes mellitus are fundamentally interrelated through this metabolic paradigm and result directly from the dysfunctional regulation of lipid second messenger generation in diabetic tissues. In Project 1 the role of altered glycolytically coupled activation of calcium-independent phospholipase A2 in myocardium will be explored with emphasis on the contractile dysfunction manifest in diabetic myocardium and the increased susceptibility of diabetic myocardium to ischemic injury. In Project 2 the role of increased glycolytic flux and augmented phospholipase A2 activity in promoting and propagating vascular response to injury and atherogenesis in the diabetic state will be examined. In Project 3 the role of calcium-independent phospholipase A2 in facilitating capacitative calcium entry into insulin secreting cells and vascular smooth muscle cells will be identified. Clinical studies in Projects 2 and 4 include identification of alterations in the lipid composition of specific cellular elements in diabetic atherosclerotic plaques and investigation of both the importance of lipid second messenger generation in ischemic human myocardium and the role of hyperglycemia and hyperinsulinemia per se in the development of coronary atherosclerosis in human subjects. Collectively, the proposed studies represent a multidisciplinary approach from the laboratory to the clinical setting designed to identify a unifying glucose mediated mechanism underlying myocardial and vascular disease in diabetes.
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