Mechanism of cardiovascular disease in premenopausal women

绝经前女性心血管疾病的发病机制

基本信息

批准号：
10530651
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
项目类别：
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/10530651
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 Leptin deficiency Mediating Menopause Mineralocorticoid Receptor Mus Obesity Obesity Related Hypertension Obesity associated cardiovascular disease Outcome Patients Persons 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 pharmacologic protective effect racial difference receptor expression reproductive restoration salt sensitive sex sociodemographics steroid hormone

项目摘要

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.

项目概要营养不良是全世界死亡和残疾的主要风险因素在美国，超过 45% 的心血管死亡患者都受到饮食风险的影响，无论其年龄、性别和年龄如何。然而，研究调查了次优的心血管后果。值得注意的是，最近有令人信服的证据表明，绝经前妇女的饮食仍然很少。育龄妇女对盐更加敏感，容易患与肥胖相关的心血管疾病与男性相比，过量食盐和肥胖会抵消绝经前的心血管疾病（CVD）高血压的优势仍然未知，在该应用的初步数据中，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 - 内皮-盐皮质激素受体（MR）轴”在盐敏感性和肥胖相关CVD中的作用我们首次鉴定了内源性盐敏感性小鼠模型 Balb/C。小鼠，它复制了人类表型，并且雌性比雄性表现出更高的盐敏感性。提供数据表明缺乏醛固酮抑制、MR 过度激活和肾上腺瘦素增加受体表达是高饮食女性性别特异性血压升高的潜在因素与此同时，我们发现瘦素是肾上腺醛固酮产生的新直接调节剂。提出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，我们发现女性的动脉更多。与雄性相比，女性和雌性小鼠更容易出现醛固酮介导的内皮功能障碍值得注意的是，我们发现内皮 MR (ECMR) 的表达高于男性和雄性动物。内皮黄体酮受体激活上调女性的 ECMR 最后，我们表明盐敏感。雌性 Balb/C 小鼠的 ECMR 表达比 C57Bl/6 背景下的雌性小鼠高 3 倍，总而言之，这些令人兴奋的新颖发现为核心假设提供了信息。该提案的内容：黄体酮诱导的 ECMR 表达和瘦素介导的肾上腺醛固酮产生合作消除女性性激素的保护作用并使育龄女性易感我们将在目标 1 中检验这一假设的具体内容。肾上腺瘦素受体对盐和肥胖相关 CVD 的贡献，而在目标 2 中我们将确定黄体酮是否通过增加 ECMR 表达而导致盐和肥胖相关的 CVD。在目标 3 中，我们将使用废弃的人体组织来研究 ECMR 水平的差异是否是造成这种差异的原因我们预计通过增加内皮 ENaCα 活性来消除盐敏感性的性别、应变和种族差异。该提案将导致确定使绝经前妇女倾向于饮食的机制相关的CVD并开辟新的治疗途径。