Estrogen receptor alpha signaling in endothelial cells exacerbates arterial stiffening via upregulation of ENaC in insulin resistant females

内皮细胞中的雌激素受体 α 信号传导通过上调 ENaC 加剧胰岛素抵抗女性的动脉硬化

• 批准号: 10152374
• 负责人: Camila Margarita Manrique Acevedo
• 金额: $ 85.84万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152374
• 关键词: Ablation; Affect; Age; Aging; Aldosterone; Amiloride; Attenuated; Biological Availability; Blood Vessels; Cardiovascular Diseases; Cell Culture Techniques; Cell Volumes; Cell surface; Characteristics; Data; Endothelial Cells; Endothelium; Estrogen Receptor alpha; Estrogens; Fatty acid glycerol esters; Female; Fructose; Functional disorder; Glucocorticoids; Human; Hypertension; In Vitro; Insulin Resistance; Knockout Mice; Measures; Mediating; Menopause; Mus; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overnutrition; Pathway interactions; Pharmacology; Phosphotransferases; Play; Postmenopause; Predisposition; Premenopause; Process; Protein-Serine-Threonine Kinases; Regulation; Risk; Role; Serum; Sex Differences; Signal Pathway; Signal Transduction; Small Interfering RNA; Stimulus; Therapeutic Agents; Tissues; Translating; Up-Regulation; Woman; Work; arterial stiffness; base; cardiovascular disorder risk; cohort; diabetic; dietary control; endothelial dysfunction; epithelial Na+ channel; experimental study; feeding; high risk; improved; in vivo; inhibitor/antagonist; knockout animal; male; men; mouse model; premature; prevent; protective effect; randomized placebo controlled trial; sex; steroid hormone; translational study; western diet

Project Summary/Abstract Arterial stiffening is a hallmark of the aging process. However, premature stiffening is often seen in hypertension, obesity, insulin resistance, and type 2 diabetes (T2D). Both men and women are affected, but women with T2D are at greater risk. As augmented arterial stiffness is an independent predictor of cardiovascular disease (CVD), the increased susceptibility of insulin-resistant (IR) and obese women to arterial stiffening may explain their higher risk for CVD. In healthy women, estrogen signaling via estrogen receptor alpha (ERα) prevents stiffening, but these effects are blunted in over-nutrition and obesity when the presence of the ER may be deleterious. Endothelial cell (EC) epithelial sodium channel (ENaC) expression increases in obese and IR female mice. Increased EC ENaC contributes to arterial stiffening and EC dysfunction, in part by lowering nitric oxide (NO) bioavailability. Aldosterone is a major ENaC stimulus, but other steroid hormones, specifically estrogen, also promote ENaC expression/function in various tissues. ENaC activity is regulated by the serum glucocorticoid inducible-kinase 1 (SGK-1) pathway. Elevated aldosterone and decreased NO bioavailability are characteristics of obese, IR and T2D women. Based on our prior work and most recent preliminary data, our hypothesis is that estrogen action through the EC ERα upregulates EC ENaC expression and activity, via SGK-1, exacerbating endothelial and arterial stiffening in obese, IR premenopausal females. The corollary to this hypothesis is that ENaC inhibition will have a greater impact on arterial stiffness in obese, premenopausal IR women than in obese IR postmenopausal women or age-matched obese, IR men. Consequently, ENaC inhibition will have a greater impact on arterial stiffness in premenopausal obese, IR women than in obese, IR men. We will measure arterial/EC stiffness in IR and obese EC-specific ERα and ENaC KO mice; in isolated ECs; and in a cohort of obese, IR women (pre and post-menopausal) and age- matched men, to accomplish the following Aims: 1) To determine whether EC ERα regulation of EC ENaC, via SGK-1, plays an important role in the genesis of accelerated endothelial and arterial stiffening in IR female mice and 2) to determine whether treatment with the ENaC inhibitor, amiloride, improves endothelial function and arterial stiffness in obese IR subjects in a randomized placebo-controlled trial. To date, the specific role of EC ERα regulation of ENaC expression/activation, in ensuing sex-related differences in arterial stiffness in obesity and insulin resistance, remains unexplored. This proposal aims to fill that gap and show that targeting ENaC activation holds extraordinary promise in reversing endothelial dysfunction and arterial stiffness in obesity and insulin resistance, and ultimately preventing cardiovascular disease, especially in women.

项目摘要/摘要 动脉僵硬是衰老过程的标志。但是，经常在 高血压，肥胖，胰岛素抵抗和2型糖尿病（T2D）。男人和女人都受到影响，但是 患有T2D的妇女的风险更大。由于增强的伪影刚度是独立的预测指标 心血管疾病（CVD），胰岛素耐药（IR）和肥胖女性对动脉的敏感性增加 加强可能会解释其更高的CVD风险。在健康的女性中，通过雌激素受体信号传导 α（ERα）防止僵硬，但是当存在时，这些作用在过度营政和肥胖症中被钝化 可能会删除er。内皮细胞（EC）上皮钠通道（ENAC）表达增加 肥胖和红外雌性小鼠。 EC ENAC增加导致动脉僵硬和EC功能障碍，部分原因是 降低一氧化氮（NO）生物利用度。醛固酮是主要的ENAC刺激，但其他类固醇激素， eNAC表达/功能在各种timsues中。 ENAC活动受 血清糖皮质激素诱导型激酶1（SGK-1）途径。高架醛固酮并改善了 生物利用度是肥胖，IR和T2D女性的特征。根据我们的先前工作以及最新的工作 初步数据，我们的假设是通过ECERα的雌激素作用上调EC ENAC表达 和活动，通过SGK-1，肥胖的肥胖症中的内皮和动脉僵硬加剧。 这一假设的推论是，ENAC抑制作用将对肥胖的动脉刚度产生更大的影响， 绝经后妇女比肥胖的红外妇女或年龄匹配的肥胖，ir男性。 因此，ENAC抑制作用将对绝经前肥胖的动脉刚度产生更大的影响 女性比肥胖的男人。我们将在IR和肥胖EC特异性ERα和 ENAC KO小鼠；在孤立的EC中；在一系列肥胖，IR妇女（绝经前后）和年龄 匹配的男人，以实现以下目的：1）确定EC ECα的EC ENAC是否调节 SGK-1在IR女性的加速内皮和动脉僵硬的起源中起重要作用 小鼠和2）确定用ENAC抑制剂治疗淀粉样蛋白是否改善内皮功能 在一项随机安慰剂对照试验中，肥胖IR受试者的动脉僵硬。迄今为止，具体角色 ECERα调节ENAC表达/激活，以确保与性别相关的动脉僵硬差异 肥胖和胰岛素抵抗仍然出乎意料。该建议旨在填补这一空白并表明目标 ENAC激活在逆转内皮功能障碍和动脉僵硬方面具有非凡的希望 肥胖和胰岛素抵抗，并最终预防心血管疾病，尤其是在女性中。