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

项目总结 肥胖影响了美国超过42%的成年人，是高血压的主要风险因素。而当 绝经前的女性通常被认为可以预防高血压和心血管疾病， 令人信服的证据表明，肥胖消除了女性性行为的保护作用，并使 女性易患血管功能障碍和高血压。肥胖相关高血压(OAH)涉及 脂肪因子瘦素在男性和女性中都存在，但通过性别特异的机制。我们已经证明了瘦素 提高男性的交感神经活性，而它刺激醛固酮的产生并导致激活 肥胖雌性小鼠内皮细胞中盐皮质激素受体(MR)信号的研究。临床数据显示 肥胖女性的醛固酮水平高得不成比例，而且对MR阻滞剂更敏感。 然而，知识上的严重差距是这些性别差异的根源。初步研究显示， 性腺切除术(GDX)缺乏女性性激素对肥胖没有额外的影响 雌性老鼠。这一新的数据表明，OAH仍然是瘦素依赖和醛固酮介导的 缺乏女性性激素，女性性激素在控制发育方面的作用有限 当然了。基于这些发现，这一提议的中心假设是女性性染色体 增强肥胖患者肾上腺瘦素-细胞色素P11B2-醛固酮轴。这一假设将在两个目标中得到检验。目标 1将检验女性性染色体易受瘦素介导的醛固酮产生的假设 还有高血压。我们将研究瘦素和醛固酮产生的控制机制，以及 注射瘦素的GDX四核心基因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 容易因瘦素和肥胖而加剧醛固酮的产生。我们将利用 我们通过获取新鲜的人类肾上腺和人类肾上腺皮质细胞来确定女性性别 肥胖使肾上腺容易产生瘦素介导的醛固酮，并研究肥胖的影响， 性别和更年期在调节醛固酮产生的信号通路上。从这些研究中，我们预计 为了确定性染色体互补在OAH机制的性别特异性中的作用以及 证明人类女性肾上腺对瘦素介导的醛固酮的产生比 一群雄性动物。该项目将在Eric Belin de Chantemèle博士和Jennifer博士的共同指导下进行 沙利文，奥古斯塔大学血管生物学中心和生理系，这是一个有着丰富历史的 成功的博士前和博士后培训。拟议的项目为期3年，拟议的 目标是在三年的资助中分配，最终在第三年结束时进行论文答辩。 我们预计，这项新提案的发现将揭开起源的面纱，并提供有关 肥胖女性高血压的性别差异的机制和改进的治疗方法。

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.