Cardiac dysfunction is a common and important manifestation of diabetes mellitus. It is well recognized that cardiomyopathy occurs frequently in diabetic patients in the absence of known cardiac risk factors. Although little is known about the pathogenesis of diabetic cardiomyopathy, evidence is emerging that cardiac dysfunction in the diabetic heart is related to perturbations in myocardial metabolism caused primarily or secondarily by insulin deficiency or resistance. In uncontrolled diabetes, the myocardial extraction and utilization of fat is markedly increased such that the diabetic heart relies almost exclusively on mitochondrial fatty acid oxidation (FAO) for its ATP requirements. Recent studies have defined an important role for the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), in the control of cardiac fatty acid utilization pathways. Our preliminary data indicates that the activation of cardiac fatty acid utilization in the diabetic heart is mediated by the PPARalpha gene regulatory pathway. Our preliminary data indicates that the activation of cardiac fatty acid utilization in the diabetic heart is mediated by the PPARalpha gene regulatory pathway. This proposal is designed to test the hypothesis that lipid metabolic alterations secondary to increased activity of PPARalpha lead to pathologic remodeling in the diabetic heart. Such pathologic remodeling could occur due top increased oxygen consumption or through toxic lipid intermediates generated by peroxisomal or mitochondrial pathways. This hypothesis will be tested by the phenotypic characterization of mice with cardiac-specific over- expression of PPARalpha (MHC-PPAR mice). First, the lipid metabolic and cardiac functional phenotypic of multiple independent lines of MHC-PPARalpha transgenic mice will be evaluated and compared with that of mice rendered diabetic via administration of streptozotocin. Second, the role of PPARalpha in the expression and severity of diabetic cardiomyopathy will be determined by altering its activity via genetically engineered loss-of-function (PPARalpha null mice) and gain- of-function (MHC-PPAR mice) in the context of three different murine models of diabetes. Lastly, the role of altered peroxisomal function in MHC-PPAR mice compared to diabetic mice. The long term goal of this project is to delineate the precise molecular and metabolic bases for diabetic cardiomyopathy including identification of specific lipid mediators of cardiac dysfunction. This work should lead to the development of novel therapeutic strategies aimed at modulating cardiac lipid metabolism to reduced the cardiovascular morbidity and morality in diabetic patients.
Showing the most recent 10 out of 180 publications
