A central theme in diabetic cardiovascular disease is the dysfunctional accumulation of lipids in critical cell-types (e.g., cardiac myocytes and macrophages) which underlie the intrinsic cardiomyopathy and accelerated atherosclerosis present in the diabetic patient. The unifying hypothesis of the program project grant is that lipid alterations in these cell types are due to fundamental changes in peroxisomal lipid flux mediated by alterations in intracellular phospholipases, PPAR mediated transcriptional regulation of critical regulatory proteins and altered lipid second messenger generation which collectively predispose candidate target cells to lipid accumulation and maladaptive pathophysiologic responses. In Project 1, we will examine the role of a novel peroxisomal calcium-independent phospholipase A2, iPLA2gamma, as a regulator of peroxisomal lipid synthesis and fatty acid beta oxidation in the cardiac myocyte. Additionally, Project 1 will examine the role of iPA2beta as a potential mediator of altered lipid metabolism and electrophysiologic dysfunction in diabetic myocardium. Dr. Kelly's Project, the role of PPARalpha as a primary determinant of the cardiac metabolic and functional phenotype present in the diabetic state will be examined utilizing mice over-expressing PPARalpha in cardiac myocyte specific fashion and a mice null for PPARalpha. Physiologic and biochemical alterations resulting from PPARalpha over-expression and the ventricular hemodynamic and metabolic abnormalities in diabetic myocardium will be compared. In Project 3, the role of altered peroxisomal lipid metabolism and intracellular phospholipase A2, activities in contributing to monocyte migration, lipid second messenger generation and lipid accumulation will be examined. The contribution of these factors in mediating the accelerated vascular response to mechanical to mechanical injury in diabetic rats will be examined. The contribution of these factors in mediating the accelerated vascular response to mechanical injury in diabetic rats will be examined. Dr. Muslig's Project the hypothesis that diabetic cardiomyopathy develops as a result of abnormal stimulation of Gq and Gi mediated signaling pathways leading to alterations in intracellular phospholipase activity, peroxisomal lipid metabolism and lipid second messenger generation will be studied. The contributions of cardiac myocyte phospholipases to G-protein signaling will be examined. Collectively, these studies represent a synergistic, targeted, multi-disciplinary investigation aimed at elucidating the role of altered lipid metabolism and second messenger generation in critical cardiovascular cell types as the primary determinants of the excessive cardiovascular mortality and morbidity in diabetic patients.
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