The Role of Cardiovascular Mineralocorticoid Receptors in Health and Disease

心血管盐皮质激素受体在健康和疾病中的作用

• 批准号: 7780010
• 负责人: GEZA FEJES-TOTH
• 金额: $ 39.98万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780010
• 关键词: Adrenal Cortex Hormones; Adrenal Glands; Adverse effects; Affinity; Agonist; Aldosterone; Binding; Biological; Blood; Blood Circulation; Blood Vessels; Blood Volume; Brain; Brain region; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Line; Cells; Chronic; Clinical Research; Colon; Corticosterone; Desire for food; Development; Disease; Endothelial Cells; Ensure; Enzymes; Epithelial; Epithelium; Exercise; Extracellular Fluid; Genes; Glucocorticoids; Goals; Health; Heart; Heart failure; Hippocampus (Brain); Hormones; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hypertension; Injury; Kidney; Knockout Mice; Lesion; Ligands; Mechanics; Mediating; Metabolism; Mineralocorticoid Receptor; Mineralocorticoids; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Organ; Pathology; Patients; Pharmaceutical Preparations; Physiological; Reaction; Relative (related person); Role; Site; Sodium Chloride; Steroid Receptors; Steroids; System; Testing; Tissues; Vascular Diseases; Vascular Smooth Muscle; body system; mortality; receptor; response; standard care

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.

描述（由申请人提供）：经典的醛固酮（Aldo）细胞位于肾脏和结肠中。然而，矿物皮质激素受体（MRS）在包括大脑，心脏和脉管系统在内的非上皮组织中也表达，但是这些MRS在心血管功能中的作用在很大程度上仍未开发。 MR对Aldo和糖皮质激素皮质醇/皮质酮（Cort）具有相同的亲和力。在上皮组织中，cort降解，从而使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，两种激素可以通过MR发起明显的，甚至相反的影响。最近的临床研究表明，除了标准护理外，还引入了MR阻滞剂（MRB）时，慢性心力衰竭（CHF）的死亡率和发病率显着改善。 MRB还减少了由于不适当的Aldo到体积状态而造成的最终器官损害，并减轻了动脉粥样硬化的血管病变。但是，介导这些有益作用的器官系统，由MRB置换的配体和潜在的分子机制仍然了解不足。我们的假设是，非上皮MRS的生理作用是防止在严重体积耗竭期间进行心血管塌陷，但在体积膨胀的情况下，它们的激活变得不良。我们还假设，在严重的体积耗竭和CHF中，MR从Cort转换为Aldo结合状态，并且该配体开关带来了心血管疾病。该项目的总体目标是将皮质类固醇在健康和疾病中的MR介导的心血管效应定位，以确定哪种激素介导了这些作用，并了解潜在的细胞和分子机制。具体而言，在AIM 1中，我们将使用遗传修饰的小鼠和CRE/LOXP系统在心脏，大脑或脉管系统中对MR进行组织特异性缺失，并检查此类小鼠对（a）严重体积耗竭的心血管适应，（b）心肌梗死和（c）机械性造成的造成机械性造成的造成机械性损伤。在AIM 2中，我们将检验以下假设：Aldo和Cort通过MR发挥不同的生物学和转录效应。我们将比较和对比Aldo和Cort的早期和晚期心血管效应，并确定对心肌细胞中这些激素的转录反应。更好地了解心血管MRS的作用以及通过这些受体启动的肾上腺类固醇引发的细胞和分子机制，可以为开发更有效的新药铺平道路，对治疗心血管疾病的不良反应较少。