MECHANISMS OF ACCELERATED VASCULAR DISEASE IN DIABETES

糖尿病血管疾病加速发生的机制

• 批准号: 6338895
• 负责人: JEFFREY E SAFFITZ
• 金额: $ 2.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338895
• 关键词: angiogenesis; arachidonate; atherosclerosis; autoradiography; cell growth regulation; cellular pathology; diabetes mellitus; electron microscopy; enzyme activity; glucose transport; glycolysis; histopathology; human tissue; immunocytochemistry; inflammation; laboratory mouse; laboratory rat; low density lipoprotein receptor; macrophage; phospholipase A2; phospholipase inhibitor; tissue /cell culture; vascular endothelium; vascular smooth muscle

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.

糖尿病患者的心血管发病率更高 死亡率比非糖尿病受试者。致命的心血管后遗症 糖尿病与固有的心肌功能障碍有关（糖尿病 心肌病”，增加了对心肌缺血的脆弱性和 加速的动脉粥样硬化，无法完全考虑 传统风险因素的基础。 该计划项目将调查 一个新颖的，统一的假设，可以联系起来增加的原因 糖尿病患者的心血管死亡率 涉及异常调节钙非依赖性磷脂酶A2 （PLA2）在心脏和血管中。 该酶的激活 糖尿病中糖酵解通量的增加介导导致增强 这种脂质第二的花生四烯酸和下游效应的释放 使心脏和血管紊乱产生的使者。 项目2 该计划项目将测试这个统一的假设 特别是糖尿病中大血管疾病的发病机理。 结合特性良好的大鼠模型 链霉菌素诱导的糖尿病和对球囊损伤的血管反应， 我们将通过不适当调节钙 - 独立的PLA2活性通过增强的糖酵解通量，糖尿病 促进新内膜增殖，内皮细胞功能障碍和 增强的血管血栓形成。 我们还将与 LDL受体 - / - 小鼠中的链蛋白酶素以确定是否糖尿病 加速动脉粥样硬化过程并表征 与钙无关的PLA2在这种作用中。 增加的亚细胞位点 糖尿病在血管内皮中引起的蛛网膜酸周转率 将确定细胞，平滑肌细胞和巨噬细胞，并 钙独立的PLA2在加速蛛网膜磷脂中的作用 糖尿病患者的炎症和增生反应期间的营业额 损伤的动脉将被特征。 我们还将测试关键原则 通过表征人类血管疾病中统一假设的假设 钙非依赖性的PLA2活性和磷脂代谢中的代谢 糖尿病患者的动脉粥样硬化病变。 结果的结果 项目将对整个目标做出重要贡献 计划项目以阐明双方的基本机制 糖尿病的心肌和血管并发症，最终 促进开发新疗法以减少致命后果 糖尿病心血管疾病。