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疾病发病率更高， 死亡率高于非糖尿病受试者。致命的心血管后遗症 糖尿病的发生与固有的心肌功能障碍有关(“糖尿病 心肌病“)，对心肌缺血的易感性增加， 加速的动脉粥样硬化不能完全解释在 在传统风险因素的基础上。该计划项目将调查 一个新的、统一的假说，将增加的不同原因联系在一起 糖尿病患者心血管死亡率与单一机制的关系 涉及钙非依赖性磷脂酶A2的异常调节 (PLA2)在心脏和血管中。该酶的激活 糖尿病患者由糖酵解通量增加所介导的 花生四烯酸的释放及其对脂质的下游影响 信使产生心脏和血管的紊乱。项目2 将检验这一统一假设，因为它与 具体涉及糖尿病大血管病变的发病机制。 结合描述良好且广泛使用的大鼠模型 链脲佐菌素诱导的糖尿病和球囊损伤后的血管反应， 我们将检验这一假设，即通过不适当地调节钙- 通过糖酵解通量增强的独立PLA2活性，糖尿病 促进新生内膜增殖，内皮细胞功能障碍，以及 增强血管的血栓形成能力。我们还将通过以下方式诱发糖尿病 链脲佐菌素在低密度脂蛋白受体-/-小鼠中的应用 加速动脉粥样硬化进程，并表征其作用 这种作用不依赖于钙离子的磷脂酶A2。亚细胞部位增加 糖尿病引起血管内皮细胞花生四烯酸代谢 将鉴定细胞、平滑肌细胞和巨噬细胞，并 钙非依赖性磷脂酶A2在加速花生四烯酰磷脂中的作用 糖尿病患者炎症和增殖性反应中的周转 损伤的动脉将被定性。我们还将测试主要原则 关于人类血管疾病的统一假说 钙非依赖性磷脂酶A_2活性与磷脂代谢 糖尿病患者的动脉粥样硬化病变。这样做的结果 该项目将对该项目的总体目标作出重要贡献 计划项目，以阐明两者背后的基本机制 糖尿病的心肌和血管并发症，最终， 促进新疗法的开发，以减少致命后果 糖尿病心血管疾病。