Mechanism of Diabetes-associated Hypertension

本研究的中心假设是，糖尿病相关的内皮功能障碍部分是由修饰的HDL、CD36和caveolin-2相互作用介导的，从而导致内皮一氧化氮合酶的抑制。糖尿病最普遍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”报告称，高血压患者发生II型糖尿病的可能性是正常患者的近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。内皮功能障碍是糖尿病引起的许多并发症的主要原因，包括高血压。内皮细胞影响血压的机制之一是通过产生一氧化氮。先前的研究表明，内皮细胞产生一氧化氮的能力在体内或体外暴露于糖尿病环境时受到损害。

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.