Origins of sex differences in the mechanisms of obesity-associated hypertension

肥胖相关高血压机制中性别差异的起源

• 批准号: 10678441
• 负责人: Candee Barris
• 金额: $ 4.12万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678441
• 关键词: Adrenal Glands; Adult; Affect; Aldosterone; Anabolism; Atropine; Biology; Blood Pressure; Blood Vessels; CYP11B2 gene; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical Data; Data; Dissociation; Endothelial Cells; Female; Four Core Genotypes; Funding; Gonadal Steroid Hormones; Health; Heart Rate; Human; Hypertension; In Vitro; Knowledge; Laboratories; Leptin; Measures; Mediating; Menopause; Mentorship; Mineralocorticoid Receptor; Modeling; Molecular; Mus; Myography; Obese Mice; Obesity; Outcome; Ovariectomy; Ovary; Phenotype; Physiology; Play; Ploidies; Premenopause; Production; Propranolol; Receptor Inhibition; Receptor Signaling; Recording of previous events; Reporting; Research; Risk Factors; Role; Sampling; Sex Chromosomes; Sex Differences; Signal Pathway; Signal Transduction; Source; Specificity; Testing; Therapeutic; Training; Universities; Vascular Diseases; Woman; adipokines; blood pressure control; blood pressure regulation; cardiovascular disorder risk; experimental study; female sex hormone; human female; hypertensive; improved; leptin receptor; male; mouse model; novel; obesity development; post-doctoral training; pre-doctoral; protective effect; response; sex; stem; steroidogenic acute regulatory protein; therapeutically effective

PROJECT SUMMARY Obesity, which affects more than 42% of adults in the US, is the leading risk factor for hypertension. While premenopausal women are commonly viewed as protected from hypertension and cardiovascular disease, compelling evidence establishes that obesity abrogates the protective effects of female sex and predisposes women to vascular dysfunction and hypertension. Obesity-associated hypertension (OAH) involves the adipokine leptin in both males and females but through sex-specific mechanisms. We have shown that leptin elevates sympathetic activity in males whereas it stimulates aldosterone production and leads to the activation of the mineralocorticoid receptor (MR) signaling in endothelial cells in obese female mice. Clinical data indicate that obese women have disproportionately high aldosterone levels and are more responsive to MR blockers. However, a critical gap in knowledge is the source of these sex differences. Preliminary studies revealed that the absence of female sex hormone production with gonadectomy (GDX) had no additional effect on obese female mice. This novel data suggest that OAH remains leptin-dependent and aldosterone-mediated in the absence of female sex hormones and that female sex steroids play a limited role in the control of the development of OAH. Based on these findings, the central hypothesis of this proposal is that female sex chromosomes potentiate the adrenal leptin-CYP11B2-aldosterone axis in obesity. This hypothesis will be tested in 2 aims. Aim 1 will test the hypothesis that female sex chromosomes predispose to leptin-mediated aldosterone production and hypertension. We will investigate the mechanisms controlling leptin and aldosterone production, as well as BP regulation and vascular function, in leptin-infused GDX four-core genotype mice, a model dissociating gonadal phenotype from sex chromosomes. Aim 2, will test the hypothesis that human female adrenals are predisposed to exacerbated aldosterone production in response to leptin and obesity. We will take advantage of our access to freshly obtained human adrenals and human adrenocortical cells to determine whether female sex and obesity predispose adrenals to leptin-mediated aldosterone production and investigate the effects of obesity, sex and menopause on the signaling pathways regulating aldosterone production. From these studies, we expect to identify a role for sex chromosome complement in the sex specificity of the mechanisms of OAH as well as demonstrate that human female adrenals are more sensitive to leptin-mediated aldosterone production than that of males. The project will be conducted under the co-mentorship of Dr. Eric Belin de Chantemèle and Dr. Jennifer Sullivan, Vascular Biology Center and Department of Physiology at Augusta University, which has a rich history of successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the proposed aims divided amongst the 3 years of funding, culminating with a dissertation defense at the end of the third year. We anticipate that findings from this novel proposal will unmask the origin and provide new information about the mechanism for sex differences in hypertension in obese women and lead to improved therapies.

项目摘要 肥胖影响了美国42%以上的成年人，是高血压的主要危险因素。而 绝经前的妇女通常被认为可以免受高血压和心血管疾病的影响， 令人信服的证据表明，肥胖消除了女性的保护作用， 女性血管功能障碍和高血压。肥胖相关性高血压（OAH）涉及 脂肪因子瘦素在男性和女性，但通过性别特异性机制。我们已经证明， 提高男性交感神经活性，同时刺激醛固酮产生并导致激活 肥胖雌性小鼠内皮细胞中盐皮质激素受体（MR）信号传导。临床数据表明 肥胖女性的醛固酮水平过高，对MR阻滞剂的反应更敏感。 然而，一个关键的知识差距是这些性别差异的根源。初步研究显示， 由于性腺切除术（GDX）导致女性性激素缺乏， 雌性老鼠这一新的数据表明，OAH仍然是瘦素依赖性和醛固酮介导的， 缺乏女性性激素，女性性类固醇在控制发育方面发挥的作用有限 的OAH。基于这些发现，这一提议的中心假设是，女性性染色体 增强肥胖症中肾上腺瘦素-CYP 11B 2-醛固酮轴。这一假设将在2个目标中进行检验。目的 1将检验女性性染色体倾向于瘦素介导的醛固酮产生的假设 和高血压。我们将研究控制瘦素和醛固酮产生的机制，以及 瘦素输注GDX四核心基因型小鼠的血压调节和血管功能， 性染色体的性腺表型。目标2，将检验人类女性肾上腺是 易受瘦素和肥胖症的影响而加剧醛固酮的产生。我们将利用 我们使用新鲜获得的人类肾上腺和人类肾上腺皮质细胞， 和肥胖使肾上腺易于产生瘦素介导的醛固酮，并研究肥胖的影响， 性别和绝经对调节醛固酮产生的信号通路的影响。根据这些研究，我们预计 确定性染色体补体在OAH机制的性别特异性中的作用， 表明人类女性肾上腺对瘦素介导的醛固酮产生比 的男性。该项目将在Eric贝林de Chantemèle博士和Jennifer博士的共同指导下进行 沙利文，血管生物学中心和生理学系在奥古斯塔大学，其中有丰富的历史 成功的博士前和博士后培训。拟议项目为期3年， 目标分为3年的资金，最终在第三年年底的论文答辩。 我们预计，这项新提议的发现将揭开其起源，并提供有关 肥胖女性高血压的性别差异机制，并导致改善治疗。