Mechanism of cardiovascular disease in premenopausal women

绝经前女性心血管疾病的发病机制

• 批准号: 10320784
• 负责人: Eric J Belin de Chantemele
• 金额: $ 53.56万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320784
• 关键词: Adrenal Glands; Affect; African American population; Age; Aldosterone; Animal Model; Animals; Arteries; Blood Pressure; Blood Vessels; CYP11B2 gene; Cardiovascular Diseases; Cardiovascular system; Caucasians; Cessation of life; Clinical; Consumption; Coronary Arteriosclerosis; Data; Development; Diet; Endothelial Cells; Endothelium; Excess Dietary Salt; Exhibits; Female; Genetic; Genetic Engineering; Human; Hypertension; Impairment; Inbred BALB C Mice; Knowledge; Leptin; Mediating; Menopause; Mineralocorticoid Receptor; Mus; Obesity; Obesity Related Hypertension; Obesity associated cardiovascular disease; Outcome; Patients; Persons; Pharmacology; Phenotype; Premenopause; Prevention; Production; Progesterone; Progesterone Receptors; Receptor Activation; Receptor Inhibition; Resistance; Risk; Risk Factors; Sampling; Sex Differences; Sodium Chloride; Stroke; Testing; Time; Vascular Diseases; Widespread Disease; Woman; adipokines; blood pressure elevation; cardioprotection; diet-induced obesity; dietary; disability; endothelial dysfunction; female sex hormone; genetic approach; high salt diet; human tissue; leptin receptor; male; men; mortality; mouse model; novel; nutrition; overexpression; protective effect; racial difference; receptor expression; reproductive; restoration; salt sensitive; sex; sociodemographics; steroid hormone

PROJECT SUMMARY Suboptimal nutrition is the leading risk factor for death and disability worldwide and accounts for accounts for more than 45% of cardiovascular death in the US. Dietary risks affect people regardless of age, sex, and sociodemographic development. However, studies investigating the cardiovascular consequences of suboptimal diet in premenopausal women remain scarce. Notably, although compelling recent evidence indicates that women of reproductive age are more salt sensitive and prone to obesity-associated cardiovascular disease (CVD) than men, the mechanisms whereby excess salt consumption and obesity negate the premenopausal advantage for hypertension remain unknown. In preliminary data for this application, we provide new evidence involving the steroid hormone progesterone, the adipokine leptin, as well as the “adrenal-aldosterone – endothelium-mineralocorticoid receptor (MR) axis” in both salt sensitivity and obesity related-CVD in premenopausal women. We identified for the first time a mouse model of endogenous salt sensitivity, the Balb/C mouse, which reproduces the human phenotype and exhibits a higher salt-sensitivity in females than males. We provide data presenting lack of aldosterone suppression, MR overactivation and increased adrenal leptin receptor expression as potential contributors to the sex-specific elevation in blood pressure in females fed a high salt diet. Concomitantly, we identified leptin as a new direct regulator of adrenal-aldosterone production and presented leptin-mediated aldosterone production and MR activation as major contributors to obesity-associated vascular dysfunction and hypertension in females. Subsequently, we show that arteries from females are more prone to aldosterone-mediated endothelial dysfunction than that of males and that both women and female mice exhibit higher expression of the endothelial MR (ECMR) than men and male animals. Remarkably, we found that endothelial progesterone receptor activation upregulates ECMR in females. Lastly, we show that salt sensitive female Balb/C mice have a 3-fold higher expression of ECMR than female mice on the C57Bl/6 background, which are known to be salt-resistant. Taken together, these exciting and novel findings inform the core hypothesis of this proposal: Progesterone-induced ECMR expression and leptin-mediated adrenal aldosterone production cooperate to abolish the protective effects of female sex hormones and predispose females of reproductive age to diet-associated CVD. We will test this hypothesis in three aims. In aim 1 we will investigate the specific contribution of adrenal leptin receptor to salt and obesity associated CVD, while in Aim 2 we will determine whether progesterone contributes to salt and obesity-associated CVD via increasing ECMR expression. Finally, in Aim 3, we will investigate using discarded human tissues whether differences in ECMR levels are responsible for sex, strain and racial differences in salt-sensitivity via increasing endothelial ENaCα activity. We anticipate that this proposal will lead to the identification of mechanisms predisposing premenopausal women to diet- associated CVD and open new avenues for treatment.

项目总结 营养不良是世界范围内死亡和残疾的主要风险因素，这是 在美国超过45%的心血管死亡病例。饮食风险影响人们，不分年龄、性别和 社会人口发展。然而，研究次优饮食对心血管后果的研究 绝经前妇女的饮食仍然很稀缺。值得注意的是，尽管最近有令人信服的证据表明 育龄女性对盐更敏感，更容易患上肥胖相关的心血管疾病 (心血管疾病)高于男性，过量食盐和肥胖否定绝经前的机制 对高血压的优势仍不清楚。在这项申请的初步数据中，我们提供了新的证据 涉及类固醇激素黄体酮、脂肪因子瘦素以及“肾上腺-醛固酮- 血管内皮细胞-盐皮质激素受体(MR)轴在盐敏感性和肥胖相关心血管疾病中的作用 绝经前的女性。我们首次发现了内源性盐敏感的小鼠模型Balb/C 老鼠，它复制了人类的表型，雌性比雄性表现出更高的盐敏性。我们 提供缺乏醛固酮抑制、MR过度激活和肾上腺瘦素增加的数据 受体表达可能是高喂养女性血压性别特异性升高的潜在因素 食盐饮食。随之而来的是，我们发现瘦素是一种新的肾上腺醛固酮生成的直接调节因子， 瘦素介导的醛固酮产生和MR激活是肥胖相关的主要因素 女性的血管功能障碍和高血压。随后，我们发现来自女性的动脉更多 更倾向于醛固酮介导的内皮功能障碍，雌性和雌性小鼠都是如此 内皮细胞MR(ECMR)的表达高于人和雄性动物。值得注意的是，我们发现 内皮孕酮受体的激活上调了女性的eCMR。最后，我们证明了盐的敏感性 在C57BL/6背景下，雌性Balb/C小鼠eCMR的表达是雌性小鼠的3倍， 它们被认为是耐盐的。综上所述，这些令人兴奋和新颖的发现构成了核心假说 孕酮诱导的eCMR表达和瘦素介导的肾上腺醛固酮的产生 合作废除女性荷尔蒙的保护作用，使育龄女性更容易受到伤害 饮食相关的心血管疾病。我们将在三个目标上检验这一假设。在目标1中，我们将调查特定的 肾上腺瘦素受体在盐和肥胖相关心血管疾病中的作用，而在目标2中，我们将确定 孕酮是否通过增加eCMR的表达而导致盐和肥胖相关的心血管疾病。最后， 在目标3中，我们将使用废弃的人体组织来研究eCMR水平的差异是否是原因 性别、品系和种族差异通过增加内皮ENaCα活性来提高盐敏感性。我们期待着 这项提议将导致识别导致绝经前妇女节食的机制-- 相关的心血管疾病，并开辟新的治疗途径。