Regulation of lipid metabolism in diabetic myocardium

Washington University, Saint Louis MO

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Abstract

The cardiac sequelae of diabetes represents the largest cause of morbidity and mortality in the diabetic population. In both Type I and Type II diabetes, an increased reliance on fatty acid substrate is present which leads to the development of an intrinsic cardiomyopathy and an increased susceptibility of diabetic myocardium to the effects of ischemia/hypoxia. During the current grant interval, we have defined the complete genomic organization and protein sequence of a novel calcium- independent phospholipase A2 (iPA2gamma), which we propose modulates energy storage (lipid accumulation) and dissipation (FA removal through heat production) in the cardiac myocyte. Accordingly, in Specific Aim 1 we will first purify iPA2gamma to homogeneity, determine its substrate specificity and ability to transacylate salient lipids in the peroxisomal compartment. In Specific Aim 2, the biochemical and pathophysiologic sequelae of alterations in myocardial iPLA2gamma activity will be examined both by characterizing mice over-expressing iPA2gamma in a cardiac myocyte specific fashion and by generating mice null for the iPA2gamma gene. The effects of both Type I and Type II diabetes on transgenic mice over-expressing and null for iPLA2gamma will be examined by focusing on the transgene-dependent alterations in hemodynamic function and lipid flux manifest in the diabetic state. Remarkably, the gene encoding iPLA2gamma cosegregates to a locus identified by positional cloning as one of the multigenic determinants of Type II diabetes in the Pima Indian population. Accordingly, we will first identify common allelic variants of the iPLA2ganma gene in the Pima Indian population and express those allelic variants in Sf9 cells to identify their biochemical sequelae. Finally, we have demonstrated that mice over-expressing iPLA2beta in a cardiac myocyte specific fashion have ischemia-induce malignant ventricular arrhythmias. Accordingly, in Specific Aim 4 we will examine the functional sequelae of iPLA2beta over-expression in both Type I and Type II models of diabetes through detailed hemodynamic electrophysiologic and biochemical characterization of these transgene mice. Covalent alterations in iPLA2beta induced by the diabetic state will be identified and characterized. Collectively, Project 1 represents a multi-disciplinary, highly synergistic, targeted proposal to identify the importance of alterations in cardiac myocyte lipid storage and utilization as a primary determinant of the excessive cardiovascular mortality and morbidity present in the diabetic patient.