The Role of Cardiovascular Mineralocorticoid Receptors in Health and Disease

描述（由申请人提供）：醛固酮（Aldo）的经典靶细胞位于肾脏和结肠中。然而，盐皮质激素受体（MR）也表达在非上皮组织，包括脑，心脏和血管，但这些MR在心血管功能中的作用仍然在很大程度上未被探索。MR对Aldo和糖皮质激素皮质醇/皮质酮（Cort）具有相同的亲和力。虽然在上皮组织中Cort被降解，从而允许Aldo占据MR，但在非上皮组织中Cort代谢较低，因此Aldo和Cort都可以结合MR。有趣的是，越来越多的证据表明这两种激素可以启动不同的，最近的临床研究表明，慢性心力衰竭（CHF）患者的死亡率和发病率显著改善，当在标准治疗之外引入MR阻滞剂（MRB）时。MRB还减少了由不适当的醛-容量状态引起的终末器官损伤，并改善动脉粥样硬化血管病变。然而，介导这些有益作用的器官系统、被MRB置换的配体和潜在的分子机制仍然知之甚少。我们的假设是，非上皮MR的生理作用是在严重的容量不足时防止心血管崩溃，但它们的激活在容量扩张的情况下变得不适应。我们还假设，在严重的容量不足和CHF的MR从Cort-转换为Aldo-结合状态，心血管适应不良是由这种配体开关。该项目的总体目标是定位健康和疾病中皮质类固醇的MR介导的心血管效应，以确定哪种激素介导这些效应，并了解潜在的细胞和分子机制。具体而言，在目标1中，我们将使用遗传修饰的小鼠和Cre/LoxP系统在心脏、脑或脉管系统中进行MR的组织特异性缺失，并检查这些小鼠对（a）严重血容量不足、（B）心肌梗死和（c）机械损伤诱导的血管病变的心血管适应。在目标2中，我们将测试的假设，奥尔多和柯特发挥不同的生物和转录的影响，通过MR。我们将比较和对比奥尔多和柯特的早期和晚期的心血管效应，并将确定这些激素在心肌细胞的转录反应。更好地了解心血管MR的作用以及肾上腺类固醇通过这些受体启动的细胞和分子机制，可以为开发更有效的新药物铺平道路，这些药物对心血管疾病的治疗具有更少的副作用。

DESCRIPTION (provided by applicant): The classical targets cells of aldosterone (Aldo) reside in the kidney and colon. However, mineralocorticoid receptors (MRs) are also expressed in non-epithelial tissues including the brain, heart and vasculature, but the role of these MRs in cardiovascular function remains largely unexplored. The MR has equal affinity for Aldo and the glucocorticoids cortisol/corticosterone (Cort). While in epithelial tissues Cort is degraded thereby allowing Aldo to occupy the MR, in non-epithelial tissues Cort metabolism is low, and thus both Aldo and Cort can bind the MR. Interestingly, there is increasing evidence that the two hormones can initiate distinct, even opposing effects through the MR. Recent clinical studies demonstrated a remarkable improvement in mortality and morbidity of patients with chronic heart failure (CHF) when MR blockers (MRBs) are introduced in addition to standard care. MRBs also reduce end-organ damage resulting from inappropriate Aldo-to-volume status, and ameliorate atherosclerotic vascular lesions. However, the organ systems that mediate these beneficial effects, the ligand(s) displaced by MRBs and the underlying molecular mechanisms remain poorly understood. Our hypothesis is that the physiological role of non-epithelial MRs is to guard against cardiovascular collapse during severe volume depletion but their activation becomes maladaptive in a setting of volume expansion. We also hypothesize that in severe volume depletion and in CHF the MR is converted from a Cort- to an Aldo-bound state, and the cardiovascular maladaptations are brought about by this ligand switch. The overall goals of this project are to localize the MR-mediated cardiovascular effects of corticosteroids in health and disease, to determine which hormone mediates these effects, and to understand the underlying cellular and molecular mechanisms. Specifically, in Aim 1 we will use genetically modified mice and the Cre/LoxP system to perform tissue-specific deletion of the MR in the heart, brain or vasculature, and examine the cardiovascular adaptation of such mice to (a) severe volume depletion, (b) myocardial infarction and (c) mechanical injury-induced vasculopathy. In Aim 2 we will test the hypothesis that Aldo and Cort exert distinct biological and transcriptional effects via the MR. We will compare and contrast both early and late cardiovascular effects of Aldo and Cort and will determine the transcriptional responses to these hormones in cardiomyocytes. A better understanding of the role of cardiovascular MRs and the cellular and molecular mechanisms that adrenal steroids initiate via these receptors could pave the way toward the development of more effective new drugs with fewer adverse effects for the treatment of cardiovascular disease.