Obesity and Diabetes induced cardiomyopathy

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DESCRIPTION (provided by applicant) In the United States, the rise in obesity and diabetes has led to a concomitant increase in the incidence of heart disease. An increased incidence of cardiovascular disease is the most common complication of non-insulin dependent diabetes (NIDDM) (1). In addition to atherosclerosis, NIDDM is associated with a specific cardiomyopathy resulting in ventricular dysfunction (1). Autopsies and animal studies have identified an increase in interstitial collagen and myocardial fibrosis which causes the physiological changes observed in the heart muscle (2). Recent studies indicate that excessive deposition of triacylglycerol (TAG) in the heart leads to apoptosis and fibrosis, providing a mechanism for the loss of cardiac function (3, 4). Glycerol-3-phosphate acyltransferase (GPAT) is, perhaps, the most important site in regulating triacylglycerol synthesis because it catalyzes the initial, committed, and rate limiting step (5). Our studies indicate, surprisingly, that compared to other organs that synthesize triacylglycerol (liver and adipose), the expression of mitochondrial GPAT protein is highest in the heart although activity is very low, suggesting that GPAT may be allosterically regulated. Our experiments also show that rat heart mitochondrial GPAT activity is up-regulated following a 48 h fast. These results, together with the findings in a recent study showing up-regulation of GPAT mRNA in the hearts of diabetic obese fa/fa rats (4), suggest that heart GPAT dysregulation under conditions of high fatty acid influx, such as diabetes, obesity, and fasting, may play an important role in the accumulation of triacylglycerol. The overall aim of this proposal is to elucidate the regulation of mitochondrial GPAT and its role in myocardial triacylglycerol accumulation, apoptosis and fibrosis.