Mineralocorticoid and estrogen receptor alpha signaling in the pathogenesis of vascular stiffness in insulin resistant females

 描述(由申请人提供)：在胰岛素抵抗的情况下，如肥胖和2型糖尿病，女性患心血管疾病(CVD)的风险显著增加。随着美国女性患糖尿病的终生风险达到40%，心血管疾病对女性的影响继续成为一个主要的健康问题。在工业化国家，高果糖和高脂肪饮食(在本提案中称为西方饮食)的消费增加是肥胖、胰岛素抵抗和2型糖尿病发展的主要驱动因素。血管系统中的胰岛素抵抗导致生物可利用的一氧化氮(NO)减少，损害内皮依赖性的扩张，并与血管僵硬有关。减少NO导致转谷氨酰胺酶2的活性增加，这是一种增加胶原交联度和血管僵硬的酶。重要的是，血管僵硬是心血管疾病的强烈预测因子，这种异常在肥胖、胰岛素抵抗和糖尿病女性中尤其普遍。患有胰岛素抵抗的女性失去了通常由雌激素信号通过雌激素受体α(ER？)提供的血管保护，我们的初步数据表明，在胰岛素抵抗的情况下，ER？信号反常地促进女性血管僵硬。此外，我们在西方饮食诱导的胰岛素抵抗雌性啮齿动物模型上的结果也表明，盐皮质激素受体(MR)阻断改善了血管胰岛素抵抗和僵硬。在胰岛素抵抗女性中，ERA-MR相互作用在血管疾病发生中的作用，特别是血管僵硬，尚未被探讨。因此，这一建议的中心假设是，在女性中，西方饮食诱导的血管胰岛素抵抗和僵硬是内皮细胞MR和ERA信号相互作用的结果，导致NO供应减少和TG2激活增加。我的提案将使用西方饮食喂养的内皮特异性MR和ERA基因敲除的新型啮齿动物模型，以及获得体内和体外血管僵硬的创新技术。在目标1中，我将确定ERA和MR相互作用的潜在机制，因为它与胰岛素代谢信号受损和喂食西方饮食的女性血管系统中没有生物利用度有关。在目标2中，我将确定ERA和MR激活在西方饮食诱导的血管僵硬的发生中的作用。在目标3中，我将研究在完整的ERA和WD诱导的胰岛素抵抗存在的情况下，内皮MR激活对性二型血管僵硬的影响。我预计，该项目的结果将对肥胖和2型糖尿病女性的血管疾病机制产生独特的见解，最终目标是将这些发现转化为治疗策略，以减少脆弱女性的心血管疾病。

 DESCRIPTION (provided by applicant): In conditions of insulin resistance such as obesity and type 2 diabetes, women display a substantially increased risk for cardiovascular disease (CVD). As the lifetime risk for women in the United States to become diabetic reaches 40%, the impact of CVD in women continues to become a major health problem. In industrialized countries, the increased consumption of a high fructose and high fat diet (named Western Diet in this proposal) is a major driver for development of obesity, insulin resistance and type 2 diabetes. Insulin resistance in the vasculature results in decreased bioavailable nitric oxide (NO), impaired endothelial dependent dilation and is associated with increased vascular stiffness. Reduced NO results in increased activity of transglutaminase 2, an enzyme that increases collagen cross-linking and vascular stiffness. Importantly, vascular stiffness is a strong predictor of CVD and this abnormality is especially prevalent in obese, insulin resistant and diabetic women. Women with insulin resistance lose vascular protection normally afforded by estrogen signaling via estrogen receptor alpha (ER¿), and our preliminary data suggest that in insulin resistant conditions, ER¿ signaling paradoxically contributes to the promotion of vascular stiffness in females. Furthermore, our results in a female rodent model of insulin resistance induced by Western Diet also demonstrate that mineralocorticoid receptor (MR) blockade improves vascular insulin resistance and stiffness. The role of the ERa-MR interaction in the genesis of vascular disease, particularly vascular stiffness, in insulin resistant females hs not been explored. Accordingly, the central hypothesis of this proposal is that in females, Western Diet-induced vascular insulin resistance and stiffness result from an interaction of endothelial cell MR and ERa signaling leading to reduce NO availability and increased TG2 activation. My proposal will use novel rodent models of endothelial specific MR and ERa knockout fed a Western Diet, as well as innovative techniques to access vascular stiffness in vivo and ex vivo. In Aim 1, I will determine mechanisms underlying the ERa and MR interaction as it relates to impaired insulin metabolic signaling and NO bioavailability in the vasculature of females fed a Western Diet. In Aim 2, I will determine the role of ERa and MR activation in the genesis of Western Diet induced vascular stiffness. In Aim 3, I will examine sexual dimorphic vascular stiffness effects of endothelial MR activation in the presence of intact ERa and WD-induced insulin resistance. I anticipate that results from this project will yield unique insights nto the mechanisms of vascular disease in obese and type 2 diabetic women, with the ultimate goal of translating these findings into therapeutic strategies to reduce CVD in vulnerable women.