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。内皮衍生一氧化氮的生物利用度降低与动脉粥样硬化的形成有关，并可能是糖尿病血管疾病发展的一个基本因素。活性氧自由基对一氧化氮的加速降解和蛋白激酶C激活对一氧化氮合酶的抑制都是导致一氧化氮减少的潜在机制。赞助商的实验室已经证实糖尿病患者和患有实验性高血糖的健康非糖尿病受试者的内皮依赖性血管扩张功能受损。进一步的实验表明，维生素C改善了内皮依赖的血管扩张，暗示了过氧化应受到的影响。可溶的谷胱甘肽依赖的抗氧化剂途径负责极性过氧化物质的解毒，也受到高血糖的不利影响，可能代表了一种特定的生理机制，部分导致糖尿病患者表现出的内皮功能受损。这项建议将研究Ebselen(一种谷胱甘肽过氧化物酶模拟物)对糖尿病患者(I型和II型)和年龄匹配的健康对照的内皮功能的影响，以确定极性过氧化是否在糖尿病的内皮功能障碍中发挥重要作用。高血糖导致蛋白激酶C亚型β2(PKCβ2)表达上调，使一氧化氮合酶磷酸化，降低其活性。这项建议还将研究LY333531，一种PKCβ2抑制剂，在I型和II型糖尿病患者和年龄匹配的健康对照组中，对前臂阻力和导管血管内皮依赖性血管扩张的作用。

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.