MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN DIABETICS

血管疾病是美国1200万糖尿病患者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率和死亡率的主要原因。 内皮源性一氧化氮的生物利用度降低与动脉粥样硬化形成有关，可能是糖尿病血管疾病发展的一个基本因素。 通过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抑制一氧化氮合酶是导致一氧化氮减少的每个潜在机制。 申办者的实验室已证明糖尿病患者和实验性高血糖的健康非糖尿病受试者的内皮依赖性血管舒张受损。 进一步的实验表明，维生素C改善了内皮依赖性血管舒张，这与超氧化物的作用有关。 负责极性过氧化物解毒的可溶性谷胱甘肽依赖性抗氧化途径也受到高血糖症的不利影响，可能是导致糖尿病中部分内皮功能受损的特定生理机制。本提案将研究依布硒啉（一种谷胱甘肽过氧化物酶模拟物）对糖尿病（I型和II型）受试者和健康、年龄匹配的对照者内皮功能的影响，以确定极性过氧化物是否在糖尿病内皮功能障碍中发挥重要作用。 高血压导致蛋白激酶C亚型β 2（PKC β 2）的上调，这可能使一氧化氮合酶磷酸化，降低其活性。该提案还将研究LY333531（一种PKC β 2抑制剂）对I型和II型糖尿病受试者以及年龄匹配的健康对照者前臂阻力和导管血管内皮依赖性血管舒张的作用。

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.