Mechanisms of CVD and Endothelial Dysfunction in Obesity

描述(由申请人提供)： 内皮细胞(EC)功能障碍发生在胰岛素抵抗过程的早期，实际上，它可能是代谢紊乱综合征的一个组成部分。我们推测，脂肪因子可能通过增加对血管紧张素Ⅱ(Ang11)的敏感性，部分通过改变磷酸肌醇-3-激酶(Pt3K)和丝裂原活化蛋白激酶(MAPK)通路之间的平衡来促进胰岛素抵抗和EC功能障碍。因此，胰岛素抵抗发展为2型糖尿病的过程与内皮细胞功能障碍进展为动脉粥样硬化的过程平行。具体目的将是确定：1)在胰岛素敏感型(IS)和胰岛素抵抗(IR)的墨西哥裔美国人(MA)中，循环脂肪因子与EC功能的关系。IR MA将包括胰岛素抵抗的谱系：早期IR、糖耐量低减和2型糖尿病。血管内皮细胞功能将通过冠脉PET扫描进行测量。2)胰岛素抵抗受试者对血管紧张素转换酶抑制剂的敏感性是否高于年龄和性别匹配的受试者，以血压、抑制血浆肾素活性、增加循环hsCRP和脂肪因子水平以及刺激血浆醛固酮水平来衡量。3)给予Angli AT1受体拮抗剂(ARB)对IR受试者胰岛素介导的葡萄糖摄取、EC功能以及循环脂肪因子和炎症标志物的影响。4)胰岛素抵抗组、胰岛素抵抗组和胰岛素抵抗组治疗前后皮下脂肪组织中炎症基因表达、MAPK和PI3K活性与胰岛素敏感性和血管内皮细胞功能的相关性。5)Zucker瘦身与肥胖大鼠模型中EC功能与胰岛素敏感性、循环脂肪因子及脂肪因子表达的相关性。这些研究结果将有助于1)确定脂肪因子改变信号机制和增加对Ang11的敏感性以损害EC功能的潜在机制；2)确定RAS抑制对脂肪因子水平和表达的影响与胰岛素介导的葡萄糖摄取和EC功能有关。这些研究可能具有直接的临床应用，因为它们承诺确定在胰岛素抵抗和EC功能障碍的频谱中，抑制RAS是必要的，以防止糖尿病和动脉粥样硬化终点的发展。如果我们要预防这两种主要疾病，早期干预是至关重要的，这两种疾病实际上可能是同一种疾病。

DESCRIPTION (provided by applicant): Endothelial cell (EC) dysfunction occurs early in the process of insulin resistance and, indeed, may be an integral component of the dysmetabolic syndrome. We hypothesize that adipokines contribute to both insulin resistance and EC dysfunction, possibly by increasing sensitivity to Angiotensin ll (Angll), in part by altering the balance between the activity of the phosphoinositol-3-kinase (Pt3K) and mitogen activated protein kinase (MAPK) pathways. As a result, the progression of insulin resistance to type 2 diabetes parallels the progression of EC dysfunction to atherosclerosis. Specific Aims will be to determine: 1) The relationship of circulating adipokines to EC function in insulin sensitive (IS) vs. insulin resistant (IR) Mexican Americans (MA). The IR MA will include the spectrum of insulin resistance: early IR, IGT, and type 2 diabetes. EC function will be measured by coronary PET scanning. 2) Whether IR subjects have increased sensitivity to AngII infusion vs. age and gender-matched IS subjects as measured by blood pressure, suppression of plasma renin activity, increasing circulating hsCRP and adipokine levels, and stimulation of plasma aldosterone 3) The effect of AnglI AT1 receptor blocker (ARB) administration on insulin-mediated glucose uptake, EC function, and circulating adipokines and inflammatory markers in IR subjects. 4) The correlations of insulin sensitivity and EC function with measurements of inflammatory gene expression, MAPK and PI3K activity in subcutaneous fat biopsies of IS vs. IR subjects and of (IR) subjects before and after treatment with an ARB. 5) The correlation of EC function with insulin sensitivity, circulating adipokines, and fat adipokine expression in the Zucker lean vs. obese rat models. The results of these investigations will help to 1) identify potential mechanisms by which adipokines alter signaling mechanisms and increase sensitivity to Angll to impair EC function and 2) determine the effect of RAS inhibition on adipokine levels and expression as related to insulin-mediated glucose uptake and EC function. These studies potentially have direct clinical applications as they promise to determine where in the spectrum of insulin resistance and EC dysfunction RAS inhibition is warranted to prevent development of the endpoints of diabetes and atherosclerosis. Early intervention is critical if we are to prevent these two major diseases, which may, indeed, be the same disease.