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; 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.

项目摘要 次优营养是全世界死亡和残疾的主要危险因素，并说明了帐户 在美国，超过45％的心血管死亡。饮食风险会影响人们，无论年龄，性别和性别如何 社会人口统计学发展。但是，研究了次优最佳后果的研究 绝经前妇女的饮食仍然很少。值得注意的是，尽管令人信服的最近证据表明 生殖年龄的妇女对盐的敏感性更高，并且容易发生肥胖相关的心血管疾病 （CVD）比男性，过量消耗和肥胖的机制否定了绝经前 高血压的优势仍然未知。在此应用程序的初步数据中，我们提供了新的证据 涉及类固醇马酮孕酮，脂肪因子瘦素以及“肾上腺醛固酮 - 盐敏感性和肥胖相关-CVD中的内皮矿物皮质激素受体（MR）轴” 绝经前妇女。我们首次确定了内源性盐灵敏度的小鼠模型BALB/C 小鼠繁殖人类表型并在女性中表现出比男性更高的盐敏感性。我们 提供缺乏醛固酮抑制，MR过度活化和肾上腺瘦素增加的数据 受体表达是女性血压特异性升高的潜在促进者 盐饮食。同时，我们确定了瘦素是肾上腺 - 醛固酮产生的新直接调节剂， 提出了瘦素介导的醛固酮的产生和MR激活，作为肥胖相关的主要贡献者 女性的血管功能障碍和高血压。随后，我们表明女性的动脉更多 比男性和女性小鼠容易发生醛固酮介导的内皮功能障碍 与男性和雄性动物相比，内皮MR（ECMR）的表达更高。值得注意的是，我们发现 内皮孕酮受体激活在女性中上调ECMR。最后，我们表明盐敏感 雌性BALB/C小鼠的ECMR表达比C57BL/6背景上的雌性小鼠高3倍， 已知是耐盐的。综上 该提案：孕酮诱导的ECMR表达和瘦素介导的肾上腺醛固酮产生 合作废除女性性恐怖的受保护作用和生殖年龄的易感性 与饮食相关的CVD。我们将以三个目标检验这一假设。在AIM 1中，我们将调查特定的 肾上腺瘦素受体对盐和肥胖相关的CVD的贡献，而在AIM 2中，我们将确定 孕酮是否通过增加ECMR表达来促进盐和肥胖相关的CVD。最后， 在AIM 3中，我们将使用丢弃的人体组织进行调查，无论ECMR水平的差异是否负责 对于性别，通过增加内皮ENACα活性，盐敏感性的应变和种族差异。 该提议将导致鉴定机制，使绝经前妇女饮食 - 相关的CVD和开放新途径进行治疗。