REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM

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PROJECT SUMMARY/ABSTRACT Diabetic cardiomyopathy is a complex disorder that emanates from the chronic and excessive use of fatty acids to fuel contractile function in diabetic myocardium due to the lack of insulin signaling and glucose uptake and utilization. The nearly exclusive use of fatty acids for fuel in diabetic myocardium results in widespread metabolomic dysregulation that precipitates multiple deleterious alterations in membrane structure and function. During the current grant interval, we have utilized enabling mass spectrometric technologies we developed to identify a plethora of novel signaling molecules in diabetic myocardium which we hypothesize contribute significantly to the bioenergetic inefficiency and maladaptive signaling in diabetic myocardium. We propose that these novel signaling molecules contribute to the increased mortality of diabetic patients suffering from acute coronary syndromes leading to myocardial infarction (MI). Moreover, the consequences of these pathologic alterations in signaling pathways in diabetic myocardium lead to the poor 5 year prognosis of diabetic patients after MI and include bioenergetic alterations that precipitate hemodynamic compromise, and promote mitochondrial dysfunction characteristic of diabetic cardiomyopathy. Lipids serve pleiotropic roles in cell function including substrate for energy production in myocardium. A primary aspect of diabetic cardiomyopathy is the maladaptive and dysfunctional integration of lipid metabolism with utilization thereby resulting in the production of toxic signaling molecules. Previously, through genetic, pharmacologic and chemical biological approaches, we have identified three major phospholipases and lipases in myocardium iPLA2ß (PNPLA9), iPLA2γ (PNPLA8), and iPLA2ζ (PNPLA2; ATGL) that likely serve as principal mediators of myocardial hemodynamic dysfunction, electrophysiologic alterations and maladaptive remodeling in diabetic myocardium. Recently, we demonstrated that iPLA2γ and its downstream signaling metabolites initiate a transformative signaling pathway which likely underlies many of the multiple deleterious changes manifest in diabetic myocardium. Accordingly, in Specific Aim 1, we will use our enabling suites of mass spectrometric technologies to identify the types and amounts of novel signaling molecules produced by this pathway and identify their functions through a systems biology approach to define their specific roles in the initiation and propagation of diabetic cardiomyopathy. In Specific Aim 2, we have identified a novel mechanism activating iPLA2ß. Accordingly, we will identify the role of activated iPLA2ß in mediating the maladaptive production of signaling metabolites in diabetic myocardium and in diabetic myocardium rendered ischemic. In Specific Aim 3, we will pursue the dramatic changes in triglyceride molecular species in diabetic myocardium which, after hydrolysis by iPLA2ζ (PNPLA2; ATGL), likely promote dysfunctional signaling in diabetic myocardium. Collectively, these studies are a synergistic multidisciplinary approach to identify the chemical mechanisms mediating diabetic cardiomyopathy using three highly relevant animal models of diabetes in conjunction with genetic loss of function mice to provide a fast track approach to drug discovery and translation of prominent pharmacologic targets to the clinic.