Mechanism of cardiovascular disease in premenopausal women

项目摘要 营养不良是全球死亡和残疾的主要风险因素， 在美国超过45%的心血管疾病死亡。饮食风险影响人们，无论年龄，性别， 社会人口发展。然而，调查次优剂量的心血管后果的研究 绝经前妇女的饮食仍然很少。值得注意的是，尽管最近令人信服的证据表明， 育龄妇女对盐更敏感，更容易患上与肥胖相关的心血管疾病 (CVD)与男性相比，过量的盐摄入和肥胖会抵消绝经前的 对高血压的益处仍不清楚。在这项应用的初步数据中，我们提供了新的证据， 包括类固醇激素孕酮，脂肪因子瘦素，以及“肾上腺-醛固酮- 血管内皮盐皮质激素受体（MR）轴在盐敏感性和肥胖相关的CVD中的作用。 绝经前妇女我们首次鉴定了内源性盐敏感性小鼠模型Balb/C， 小鼠，其复制人类表型，并且雌性比雄性表现出更高的盐敏感性。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 受体表达作为高血压女性性别特异性升高的潜在贡献者 盐饮食。与此同时，我们确定瘦素是一种新的肾上腺醛固酮生成的直接调节因子， 提出瘦素介导的醛固酮产生和MR激活是肥胖相关的 女性血管功能障碍和高血压。随后，我们发现，女性的动脉 更容易发生醛固酮介导的内皮功能障碍，比男性和女性和女性小鼠 显示出比人和雄性动物更高的内皮MR（ECMR）表达。值得注意的是，我们发现， 内皮孕酮受体激活上调女性ECMR。最后，我们表明，盐敏感 雌性Balb/C小鼠的ECMR表达比C57 B1/6背景下的雌性小鼠高3倍， 其已知是耐盐的。综合起来，这些令人兴奋和新颖的发现告知核心假设 孕酮诱导的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，使育龄女性易受感染 饮食相关的心血管疾病我们将从三个方面来检验这一假设。在目标1中，我们将研究具体的 肾上腺瘦素受体对盐和肥胖相关的CVD的作用，而在目标2中，我们将确定 孕酮是否通过增加ECMR表达而导致盐和肥胖相关的CVD。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 通过增加内皮细胞ENaCα活性来研究盐敏感性的性别、品系和种族差异。我们预计 这一建议将导致确定绝经前妇女饮食的易感机制- 相关的心血管疾病，并开辟新的治疗途径。

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.