MECHANISMS OF ACCELERATED VASCULAR DISEASE IN DIABETES

糖尿病患者的心血管发病率更高， 死亡率高于非糖尿病患者。致命的心血管后遗症 糖尿病的发病与内在心肌功能障碍有关（“糖尿病 心肌病”），增加心肌缺血的脆弱性， 加速的动脉粥样硬化形成不能完全解释在 传统的风险因素。 本项目将调查 一个新颖的，统一的假设，连接不同的原因增加 糖尿病患者的心血管死亡率与单一机制 涉及钙非依赖性磷脂酶A2的异常调节 （PLA 2）在心脏和血管中。 这种酶的激活 糖尿病中糖酵解通量增加介导的 花生四烯酸的释放和这种脂质的下游效应 信使产生心脏和血管紊乱。 计划2 该计划项目将测试这一统一的假设，因为它涉及 特别是糖尿病大血管疾病的发病机制。 结合良好表征和广泛使用的大鼠模型， 链脲霉素诱导的糖尿病和血管对球囊损伤的反应， 我们将检验一个假设，即通过不适当地调节钙- 通过增强糖酵解通量的独立PLA 2活性，糖尿病 促进新生内膜增殖、内皮细胞功能障碍， 增强血管血栓形成性。 我们还将诱发糖尿病， 在LDL受体-/-小鼠中的链脲佐菌素，以确定糖尿病是否 加速动脉粥样硬化过程并表征 钙非依赖性PLA 2在这种作用中。 增加的亚细胞部位 糖尿病诱导血管内皮细胞花生四烯酸更新 细胞、平滑肌细胞和巨噬细胞， 钙非依赖性磷脂酶A2在加速花生四烯酸磷脂中的作用 糖尿病患者炎症和增殖反应期间的转换 将表征损伤的动脉。 我们还将测试关键原则 人类血管疾病的统一假设， 钙非依赖性PLA 2活性和磷脂代谢 糖尿病患者的动脉粥样硬化病变。 的结果 该项目将为实现《公约》的总体目标作出重要贡献。 项目旨在阐明两者背后的基本机制 糖尿病的心肌和血管并发症， 促进新疗法的开发，以减少致命后果 糖尿病性心血管疾病

Patients with diabetes suffer greater cardiovascular morbidity and mortality than non-diabetic subjects. The lethal cardiovascular sequelae of diabetes are related to intrinsic myocardial dysfunction ("diabetic cardiomyopathy"), increased vulnerability to myocardial ischemia and accelerated atherogenesis which cannot be fully accounted for on the basis of traditional risk factors. This Program Project will investigate a novel, unifying hypothesis that links the diverse cause of increased cardiovascular mortality in diabetic patients to a single mechanism involving abnormal regulation of calcium-independent phospholipase A2 (PLA2) in the heart and blood vessels. Activation of this enzyme mediated by increased glycolytic flux in diabetes leads to enhanced release of arachidonic acid and downstream effects of this lipid second messenger to produce both cardiac and vascular derangements. Project 2 of the Program Project will test this unifying hypothesis as it pertains specifically to the pathogenesis of macrovascular disease in diabetes. Combining the well characterized and widely used rat models of streptozotocin-induced diabetes and vascular response to balloon injury, we will test the hypothesis that by inappropriately regulating calcium- independent PLA2 activity through enhanced glycolytic flux, diabetes promotes neointimal proliferation, endothelial cell dysfunction, and enhanced vascular thrombogenicity. We will also induce diabetes with streptozotocin in LDL receptor -/- mice to determine whether diabetes accelerates the atherogenic process and to characterize the role of calcium-independent PLA2 in this effect. Subcellular sites of increased arachidonic acid turnover induced by diabetes in vascular endothelial cells, smooth muscle cells and macrophages will be identified and the role of calcium-independent PLA2 in accelerated arachidonoyl phospholipid turnover during the inflammatory and proliferative responses of diabetic arteries to injury will be characterized. We will also test key tenets of the unifying hypothesis in human vascular disease by characterizing calcium-independent PLA2 activity and phospholipid metabolism in atherosclerotic lesions from diabetic patients. The results of this project will contribute importantly to the overall objective of the Program Project to elucidate fundamental mechanisms that underlie both the myocardial and vascular complications of diabetes and, ultimately, facilitate development of new therapy to diminish the lethal consequences of diabetic cardiovascular disease.