Mechanism of Diabetes-associated Hypertension

在这个提议中要测试的中心假设是，糖尿病相关的内皮功能障碍部分是由修饰的HDL、CD 36和小窝蛋白-2的相互作用介导的，这导致内皮一氧化氮合酶的抑制。糖尿病最常见和最致命的并发症之一是心血管疾病。最近的“社区动脉粥样硬化风险研究”报告说，高血压患者患II型糖尿病的可能性是血压正常患者的近2.5倍。此外，英国前瞻性糖尿病研究和心脏结局预防评估表明，降低糖尿病患者的血压可大大降低几种心血管疾病的风险。内皮功能障碍主要涉及糖尿病引起的许多并发症，包括高血压。内皮细胞影响血压的机制之一是产生一氧化氮。先前的研究已经证明，当在体外或体内暴露于糖尿病环境时，内皮细胞产生一氧化氮的能力受到损害。 糖尿病可以抑制一氧化氮的产生，从而减少 血管的血管舒张还没有被很好地理解。一个有趣的可能性是糖尿病血清可能通过细胞表面受体如CD 36起作用。此外，初步数据表明，从糖尿病人或小鼠的血清中分离的HDL将以CD 36和小窝蛋白-2依赖性方式抑制一氧化氮的产生。本研究的目的是确定糖尿病患者HDL、CD 36和小窝蛋白-2相互作用导致内皮型一氧化氮合酶抑制的机制。目标1：确定CD 36和小窝蛋白-2内允许这两种蛋白质结合并随后抑制内皮一氧化氮合酶的结构域。目的2：探讨小窝蛋白-2的磷酸化和酰化在内皮型一氧化氮合酶抑制中的作用。目的3：探讨糖尿病患者HDL/CD 36/caveolin-2相互作用抑制内皮型一氧化氮合酶的机制。目的4：确定是否去除CD 36或 来自leprdb无效小鼠（II型糖尿病的小鼠模型）的小窝蛋白-2保护内皮一氧化氮合酶活性和血管对刺激一氧化氮产生的激动剂的反应性。

The central hypothesis to be tested in this proposal is that diabetes-associated endothelial dysfunction is mediated in part by the interaction of modified HDL, CD36 and caveolin-2 which results in the inhibition of endothelial nitric oxide synthase. One of the most prevalent and deadly complications of diabetes is cardiovascular disease. The recent "Atherosclerosis Risk in Communities Study" reported that the development of type II diabetes was nearly 2.5 times more likely in patients with hypertension than in normotensive patients. In addition, the UK Prospective Diabetes Study and the Heart Outcomes Prevention Evaluation have demonstrated that lowering blood pressure in diabetic patients greatly lessens the risk of several cardiovascular diseases. Endothelial dysfunction is centrally involved in many of the complications caused by diabetes, including hypertension. One of the mechanisms by which endothelial cells influence blood pressure is by the generation of nitric oxide. Previous studies have demonstrated that the ability of endothelial cells to generate nitric oxide is compromised when exposed either in vitro or in vivo to a diabetic environment. The mechanisms by which diabetes can inhibit nitric oxide generation and thus decrease the vasodilation of a vessel are not well understood. One intriguing possibility is that the diabetic serum may be acting through a cell surface receptor such as CD36. In addition, preliminary data demonstrate that HDL isolated from the serum of diabetic humans or mice will inhibit the generation of nitric oxide in a CD36 and caveolin-2 dependent manner. The goal of the proposed studies is to determine the mechanism(s) whereby the interaction of diabetic HDL, CD36 and caveolin-2 results in the inhibition of endothelial nitric oxide synthase. Aim 1: To determine the domain(s) within CD36 and caveolin-2 that permits the two proteins to associate and subsequently inhibit endothelial nitric oxide synthase. Aim 2: To determine the role of phosphorylation and acylation of caveolin-2 in the inhibition of endothelial nitric oxide synthase. Aim 3: To determine the mechanism(s) whereby diabetic HDL/CD36/caveolin-2 interaction inhibits endothelial nitric oxide synthase. Aim 4: To determine if the removal of CD36 or caveolin-2 from leprdb null mice (a mouse model of type II diabetes) protects endothelial nitric oxide synthase activity and vascular responsiveness to agonists that stimulates nitric oxide generation.