MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN DIABETICS

糖尿病患者内皮功能障碍的机制

• 批准号: 6183658
• 负责人: JOSHUA A BECKMAN
• 金额: $ 13.05万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-13 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183658
• 关键词: antioxidants; blood flow measurement; cardiovascular disorder; cardiovascular function; clinical research; diabetes mellitus; enzyme inhibitors; glutathione peroxidase; human subject; hyperglycemia; insulin dependent diabetes mellitus; isozymes; methacholine; nitric oxide; nitric oxide synthase; nitroferricyanide; noninsulin dependent diabetes mellitus; oxidative stress; plethysmography; protein kinase C; ultrasonography; vascular endothelium; vascular resistance; vasodilation; vein occlusion

Vascular disease is the principal cause of death and disability among the 12 million patients in the United States with diabetes mellitus. Macrovascular complications, including myocardial infarction, stroke, and amputation are the leading cause of morbidity and mortality among this cohort of patients. Reduced bioavailability of endothelium-derived nitric oxide has been implicated in atherogenesis and may be a fundamental factor in the development of vascular disease in diabetes. Increased degradation of nitric oxide by reactive oxygen radicals and inhibition of nitric oxide synthase via activation of protein kinase C are each potential mechanisms to account for decreased nitric oxide. The sponsor's laboratory has demonstrated impaired endothelium-dependent vasodilation in patients with diabetes mellitus and in healthy, nondiabetic subjects with experimental hyperglycemia. Further experiments showed that vitamin C improved endothelium-dependent vasodilation implicating a culpable role for superoxide. The soluble, glutathione-dependent antioxidant pathway, responsible for detoxification of polar peroxides, is also adversely affected by hyperglycemia and may represent a specific physiologic mechanism causing, in part, the impaired endothelial function demonstrated in diabetes mellitus. This proposal will examine the effect of ebselen, a glutathione peroxidase mimetic on endothelial function in subjects with diabetes mellitus (type I and type II) and healthy, age-matched controls to determine if polar peroxides play an important role in endothelial dysfunction in diabetes. Hyperglycemia causes the up-regulation of protein kinase C isoform beta2 (PKC beta2) which may phosphorylate nitric oxide synthase, reducing its activity. This proposal will also examine the role of LY333531, a PKC beta2 inhibitor, on endothelium-dependent vasodilation in forearm resistance and conduit vessels in subjects with type I and type II diabetes mellitus and age-matched health controls.

在美国1200万糖尿病患者中，血管疾病是导致死亡和残疾的主要原因。大血管并发症，包括心肌梗死、中风和截肢是这组患者发病和死亡的主要原因。内皮源性一氧化氮的生物利用度降低与动脉粥样硬化有关，可能是糖尿病血管疾病发展的一个基本因素。活性氧自由基增加一氧化氮的降解和通过激活蛋白激酶C抑制一氧化氮合酶都是导致一氧化氮减少的潜在机制。申办者的实验室已经证明糖尿病患者和健康的实验性高血糖的非糖尿病受试者的内皮依赖性血管舒张功能受损。进一步的实验表明，维生素C改善了内皮依赖性血管舒张，暗示了超氧化物的罪魁祸首。可溶性的依赖谷胱甘肽的抗氧化途径，负责极性过氧化物的解毒，也受到高血糖的不利影响，并且可能代表一种特定的生理机制，部分导致糖尿病中内皮功能受损。本研究将在糖尿病患者（I型和II型）和健康、年龄匹配的对照组中检测类似谷胱甘肽过氧化物酶的依布selen对内皮功能的影响，以确定极性过氧化物是否在糖尿病患者内皮功能障碍中起重要作用。高血糖引起蛋白激酶C异构体β 2 （PKC β 2）的上调，使一氧化氮合酶磷酸化，降低其活性。该提案还将研究PKC β 2抑制剂LY333531在I型和II型糖尿病患者以及年龄匹配的健康对照者的前臂阻力和导管血管内皮依赖性血管舒张中的作用。