Mineralocorticoid Receptors in Cardiovascular Biology

心血管生物学中的盐皮质激素受体

• 批准号: 6899075
• 负责人: Iris Z Jaffe
• 金额: $ 12.74万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899075
• 关键词: ACE inhibitors; Adenoviridae; aldosterone; angiotensin II; cardiovascular disorder; cardiovascular pharmacology; cell line; cell proliferation; corticosteroid receptors; endothelin; gene expression; genetic regulatory element; hormone regulation /control mechanism; immunofluorescence technique; myocardial ischemia /hypoxia; polymerase chain reaction; protein localization; receptor expression; reporter genes; spironolactone; transfection /expression vector; vascular endothelium; vascular smooth muscle; western blottings

DESCRIPTION (provided by applicant): This proposal explores the expression and function of the mineralocorticoid receptor (MR) in vascular biology. Aldosterone is synthesized by both the adrenal cortex and by vascular cells following angiotensin-2 (All) stimulation or vascular injury. Aldosterone is now recognized to directly cause endothelial damage and VSMC proliferation. Aldosterone, like all steroid hormones, binds to a ligand-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Clinical and animal studies both show that aldosterone directly effects blood vessels. Angiotensin converting enzyme (ACE) inhibitors, a mainstay of cardiovascular therapy, inhibit All and aldosterone production. In large heart failure trials, ACE inhibitors consistently reduce both LV remodeling and, surprisingly, recurrent ischemic events. Furthermore, MR antagonists decrease myocardial infarctions and overall mortality in coronary artery disease and heart failure patients independent of any renal effects. Abundant data show that aldosterone is both a stimulant of endothelin (ET-1) production by vascular cells and a potent smooth muscle cell (VSMC) mitogen. Based on these and related data, we propose to test the hypothesis that aldosterone activates functional mineralocorticoid receptors in VSMC, increases production of endothelin, and promotes VSMC proliferation. The applicant's new preliminary data demonstrate expression of functional MR in human VSMC. Three Specific Aims are proposed to investigate the mechanism of aldosterone action on VSMCs (SA1); direct, MR-dependent effects of aldosterone on VSMC ET-1 gene expression (SA2); and the role of MR and endothelin in aldosterone mediated VSMC proliferation (SA3). The proposal uses state-of-the-art molecular and cellular approaches and specialized resources developed by the Sponsor's laboratory. The candidate is a M.D.-Ph.D with extensive training in the nuclear hormone receptor field, now completing subspecialty training in cardiovascular medicine. The sponsor is an established cardiovascular physician-scientist with a major laboratory program in the molecular biology of steroid hormone receptor actions in the cardiovascular system. The proposed training is expected to provide training in vascular biology and establish the independent career of an evolving cardiovascular physician-scientist. The studies described will contribute to understanding of the molecular mechanism of aldosterone actions on the vasculature, and the beneficial effects of ACE inhibitors on ischemic cardiovascular events. The studies may also lead to new targets for the therapy of vascular diseases.

描述（由申请人提供）： 该提案探讨了盐皮质激素受体（MR）在血管生物学中的表达和功能。醛固酮由肾上腺皮质和血管紧张素 2 (All) 刺激或血管损伤后的血管细胞合成。醛固酮现已被认为可直接引起内皮损伤和 VSMC 增殖。与所有类固醇激素一样，醛固酮与配体激活的转录因子结合，该转录因子是核激素受体超家族的成员。临床和动物研究均表明醛固酮直接影响血管。血管紧张素转换酶 (ACE) 抑制剂是心血管治疗的支柱，可抑制 All 和醛固酮的产生。在大型心力衰竭试验中，ACE 抑制剂持续减少左心室重构，并且令人惊讶地减少复发性缺血事件。此外，MR 拮抗剂可降低冠状动脉疾病和心力衰竭患者的心肌梗塞和总体死亡率，而与任何肾脏影响无关。大量数据表明，醛固酮既是血管细胞产生内皮素（ET-1）的刺激剂，又是有效的平滑肌细胞（VSMC）有丝分裂剂。基于这些和相关数据，我们建议检验醛固酮激活 VSMC 中功能性盐皮质激素受体、增加内皮素产生并促进 VSMC 增殖的假设。申请人的新初步数据证明了功能性MR在人类VSMC中的表达。提出了三个具体目标来研究醛固酮对 VSMC（SA1）的作用机制；醛固酮对 VSMC ET-1 基因表达 (SA2) 的直接、MR 依赖性影响；以及 MR 和内皮素在醛固酮介导的 VSMC 增殖 (SA3) 中的作用。该提案使用了最先进的分子和细胞方法以及申办者实验室开发的专业资源。该候选人是一位医学博士-博士，在核激素受体领域接受过广泛的培训，目前正在完成心血管医学的亚专业培训。申办者是一位知名的心血管内科医生兼科学家，其主要实验室项目涉及心血管系统中类固醇激素受体作用的分子生物学。拟议的培训预计将提供血管生物学方面的培训，并建立不断发展的心血管医师科学家的独立职业生涯。所描述的研究将有助于了解醛固酮对脉管系统作用的分子机制，以及 ACE 抑制剂对缺血性心血管事件的有益作用。这些研究还可能为血管疾病的治疗带来新的靶点。