Obesity and Diabetes induced cardiomyopathy

描述（由申请人提供） 在美国，肥胖和糖尿病的增加导致了一个伴随的问题， 心脏病发病率的增加。的发生率增加 心血管疾病是非胰岛素依赖型糖尿病最常见的并发症。 糖尿病（NIDDM）（1）。除动脉粥样硬化外，NIDDM还与 导致心室功能障碍的特定心肌病（1）。尸检 动物研究已经确定了间质胶原的增加， 心肌纤维化，其引起在心肌细胞中观察到的生理变化。 心肌（2）。最近的研究表明， 心脏中的甘油三酯（TAG）导致细胞凋亡和纤维化， 心脏功能丧失的机制（3，4）。甘油-3-磷酸 酰基转移酶（GPAT）可能是调节 三酰甘油的合成，因为它催化的初始，承诺，和速率 限制步骤（5）。令人惊讶的是，我们的研究表明，与其他研究相比， 合成三酰甘油的器官（肝脏和脂肪）， 线粒体GPAT蛋白在心脏中最高，尽管活性非常低。 低，表明GPAT可能是变构调节。我们的实验也 显示大鼠心脏线粒体GPAT活性在48 h快。这些结果，以及最近一项研究的发现， 糖尿病肥胖fa/fa大鼠心脏中GPAT mRNA的上调（4）， 提示在高脂肪酸条件下心脏GPAT失调 流入，如糖尿病，肥胖和禁食，可能在 甘油三酯的积累。本建议的总体目标是 阐明线粒体GPAT的调节及其在心肌细胞凋亡中的作用， 三酰甘油积累、细胞凋亡和纤维化。

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.