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: 10636948
• 负责人: Camila Margarita Manrique Acevedo
• 金额: $ 61.49万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636948
• 关键词: Ablation; Acceleration; 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; Estrogen decline; Estrogens; Fatty acid glycerol esters; Female; Fructose; Functional disorder; Glucocorticoids; Human; Hypertension; In Vitro; Insulin Resistance; Knockout Mice; Measures; Mediating; Mus; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overnutrition; Pathway interactions; Phosphotransferases; Play; Postmenopause; Predisposition; Premenopause; Process; Protein-Serine-Threonine Kinases; Regulation; Risk; Role; Serine; Serum; Sex Differences; Signal Pathway; Signal Transduction; Small Interfering RNA; Stimulus; Therapeutic Agents; Tissues; Translating; Up-Regulation; Woman; Work; arterial stiffness; cardiovascular disorder risk; cohort; diabetic; dietary control; endothelial dysfunction; epithelial Na+ channel; experimental study; feeding; high risk; improved; in vivo; inhibitor; knockout animal; male; men; mouse model; pharmacologic; 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 动脉硬化是衰老过程的一个标志。然而，过早僵硬经常见于 高血压、肥胖、胰岛素抵抗和2型糖尿病(T2D)。男性和女性都会受到影响，但 患有T2D的女性风险更大。AS增强的动脉僵硬是一个独立的预测因子 心血管疾病(CVD)、胰岛素抵抗(IR)和肥胖女性对动脉粥样硬化的易感性增加 僵硬可能解释了他们患心血管疾病风险较高的原因。在健康女性中，雌激素通过雌激素受体传递信号 阿尔法(ERα)可防止肌肉僵硬，但这些作用在营养过剩和肥胖时会减弱 ER的危害可能是有害的。血管内皮细胞上皮钠通道(ENaC)表达增加 肥胖和IR雌性小鼠。EC ENaC增加导致动脉硬化和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ENaC的主要刺激因素，但其他类固醇激素， 具体地说，雌激素还能促进ENaC在各种组织中的表达/功能。ENAC活动受以下因素调节 血清糖皮质激素诱导的蛋白激酶-1(SGK-1)途径。醛固酮升高和一氧化氮降低 生物利用度是肥胖、IR和T2D女性的特征。基于我们之前的工作和最近的工作 初步数据，我们的假设是雌激素通过EC ERα上调EC ENaC的表达 而通过SGK-1的活性，加剧了肥胖、IR绝经前女性的内皮和动脉硬化。 这一假设的推论是，抑制ENaC将对肥胖者的动脉僵硬有更大的影响， 绝经前IR女性高于肥胖IR女性或年龄匹配的肥胖IR男性。 因此，抑制ENaC对绝经前肥胖者的动脉僵硬有更大的影响。 女性比肥胖、IR男性多。我们将测量IR和肥胖EC特异性ERα的动脉/EC硬度 ENAC KO小鼠；在分离的ECs中；在肥胖、IR妇女(绝经前和绝经后)和年龄队列中- 配对男性，以实现以下目的：1)确定EC ERα是否通过 SGK-1在女性胰岛素抵抗患者血管内皮细胞加速和动脉硬化发生中的重要作用 2)确定ENaC抑制剂阿米洛利治疗是否改善血管内皮细胞功能 在一项随机的安慰剂对照试验中，肥胖的IR受试者的动脉僵硬。到目前为止，具体的作用是 EC ERα对ENaC表达/激活的调节，以及由此导致的性别相关动脉僵硬的差异 肥胖症和胰岛素抵抗，仍未被研究。这项提议旨在填补这一空白，并表明 ENAC激活在逆转血管内皮功能障碍和动脉僵硬方面具有非凡的前景 肥胖和胰岛素抵抗，并最终预防心血管疾病，特别是在妇女中。

项目成果

Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

性和饮食引起的体重减轻对 2 型糖尿病血管胰岛素敏感性的影响。

• DOI: 10.1152/ajpregu.00249.2022
• 发表时间: 2023
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Manrique-Acevedo,Camila;Soares,RogerioN;Smith,JamesA;Park,LaurenK;Burr,Katherine;Ramirez-Perez,FranciscoI;McMillan,NeilJ;Ferreira-Santos,Larissa;Sharma,Neekun;Olver,TDylan;Emter,CraigA;Parks,ElizabethJ;Limberg,JacquelineK
• 通讯作者: Limberg,JacquelineK

Role of adropin in reducing arterial stiffness in type 2 diabetes.

adropin 在降低 2 型糖尿病动脉僵硬度方面的作用。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Jurrissen,ThomasJ;Ramirez-Perez,FranciscoI;Cabral,FranciscoJ;McMillan,NeilJ;Fujie,ShumpeiJ;Butler,AndrewA;Banerjee,Subhashis;Sacks,HowardS;Manrique-Acevedo,Camila;Martinez-Lemus,LuisA;Padilla,Jaume
• 通讯作者: Padilla,Jaume

Young Women Are Protected Against Vascular Insulin Resistance Induced by Adoption of an Obesogenic Lifestyle.

年轻女性可以免受因采用致胖生活方式而引起的血管胰岛素抵抗。

• DOI: 10.1210/endocr/bqac137
• 发表时间: 2022
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Smith,JamesA;Soares,RogerioN;McMillan,NeilJ;Jurrissen,ThomasJ;Martinez-Lemus,LuisA;Padilla,Jaume;Manrique-Acevedo,Camila
• 通讯作者: Manrique-Acevedo,Camila

Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity.

2 型糖尿病中内皮 HSP72 并未减少，也不是内皮胰岛素敏感性的关键决定因素。

• DOI: 10.1152/ajpregu.00006.2022
• 发表时间: 2022
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Pettit-Mee,RyanJ;Power,Gavin;Cabral-Amador,FranciscoJ;Ramirez-Perez,FranciscoI;Soares,RogerioN;Sharma,Neekun;Liu,Ying;Christou,DemetraD;Kanaley,JillA;Martinez-Lemus,LuisA;Manrique-Acevedo,Camila;Padilla,Jaume
• 通讯作者: Padilla,Jaume

Endothelial Glycocalyx.

• DOI: 10.1002/cphy.c210029
• 发表时间: 2022-08-23
• 期刊: COMPREHENSIVE PHYSIOLOGY
• 影响因子: 5.8
• 作者: Foote, Christopher A.;Soares, Rogerio N.;Ramirez-Perez, Francisco, I;Ghiarone, Thaysa;Aroor, Annayya;Manrique-Acevedo, Camila;Padilla, Jaume;Martinez-Lemus, Luis
• 通讯作者: Martinez-Lemus, Luis