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

盐皮质激素和雌激素受体α信号在胰岛素抵抗女性血管僵硬发病机制中的作用

• 批准号: 9103221
• 负责人: Camila Margarita Manrique Acevedo
• 金额: $ 16.65万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103221
• 关键词: Animals; Atomic Force Microscopy; Bioavailable; Biological Availability; Blood Vessels; Cardiovascular Diseases; Collagen; Consumption; Data; Developed Countries; Development; Diet; Endothelial Cells; Enzymes; Estrogen Receptor alpha; Estrogens; Event; Exhibits; Female; Fibrosis; Figs - dietary; Fructose; Genetic; Genetic Transcription; Goals; Gonadal Steroid Hormones; Health; High Fat Diet; Hormone replacement therapy; Inflammatory; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Laboratories; Metabolic; Mineralocorticoid Receptor; Modeling; Mus; Names; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pathogenesis; Pathway interactions; Physiological; Play; Postmenopause; Production; Receptor Activation; Receptor Signaling; Relaxation; Research Proposals; Resistance; Risk; Rodent Model; Role; Signal Transduction; Techniques; Testing; Therapeutic; Translating; Ultrasonography; United States; Vascular Diseases; Vasodilation; Vasomotor; Woman; Work; cardiovascular disorder risk; cardiovascular risk factor; crosslink; diabetic; feeding; improved; in vivo; indexing; innovation; insight; insulin signaling; lifetime risk; male; men; novel; response; sex; therapeutic development; transglutaminase 2; translational study; vascular inflammation; western diet

 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.

 描述（由适用提供）：在胰岛素抵抗（例如肥胖症和2型糖尿病）的情况下，女性表现出心血管疾病（CVD）的风险大大增加。随着美国妇女糖尿病患者的终生风险达到40％，CVD对妇女的影响继续成为主要的健康问题。工业化国家，高果糖和高脂肪饮食的消费量增加（在此提案中称为西方饮食）是肥胖，胰岛素抵抗和2型糖尿病的主要驱动力。脉管系统中的胰岛素耐药性可改善生物利用一氧化氮（NO），内皮依赖性词典受损，并且与血管僵硬的增加有关。降低了转谷氨酰胺酶2的活性增加，这是一种增加胶原蛋白交联和血管刚度的酶。重要的是，血管僵硬是CVD的有力预测指标，这种异常在肥胖，胰岛素抵抗和糖尿病女性中尤为普遍。具有胰岛素抵抗的妇女通常通过雌激素受体α（ER¿）提供了通常由雌激素信号传导提供的血管保护，我们的初步数据表明，在胰岛素耐药条件下，ER？矛盾的信号矛盾地有助于促进女性血管僵硬。此外，我们在西方饮食引起的胰岛素抵抗的雌性啮齿动物模型中的结果还表明，矿物皮质激素受体（MR）阻断可提高血管胰岛素抵抗和僵硬。没有探索ERA-MR相互作用在血管疾病的起源（尤其是血管僵硬）中的作用，在胰岛素抵抗性雌性HS中的作用未探索。根据该提议的中心假设是，在女性中，西方饮食引起的血管胰岛素抵抗和僵硬是由于内皮细胞MR和ERA信号的相互作用而导致的，导致没有降低可用性和TG2激活增加。我的建议将使用内皮特异性MR和ERA敲除的新型啮齿动物模型喂食西方饮食，以及创新的技术，以获取体内和Ex Vivo的血管僵硬。在AIM 1中，我将确定与胰岛素代谢信号受损相关的ERA和MR相互作用的基础机制，并且在喂食西方饮食的女性脉管系统中没有生物利用度。在AIM 2中，我将确定ERA和MR激活在西方饮食的起源中的作用，引起血管僵硬。在AIM 3中，我将在完整的ERA和WD诱导的胰岛素抵抗的情况下检查内皮MR激活的性双态血管刚度。我预计该项目的结果将产生独特的见解，从而为肥胖和2型糖尿病妇女的血管疾病机制提供了独特的见解，其最终目标是将这些发现转化为治疗策略，以减少弱势妇女的CVD。