Mineralocorticoid receptor and abdominal aortic aneurysm

盐皮质激素受体与腹主动脉瘤

基本信息

批准号：
9173466
负责人：
MING C GONG
金额：
$ 51.96万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-15 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173466
关键词：
Abdomen Abdominal Aortic Aneurysm Acetates Affect Age Agonist Aldosterone Animal Genetics Animal Model Aorta Aortic Aneurysm Attenuated Basic Science Biochemical Cardiovascular Diseases Cardiovascular system Cell Membrane Permeability Cessation of life Clinic Clinical Country Deoxycorticosterone Diagnosis Disease Elastin Eligibility Determination Endothelial Cells Etiology Free Radical Scavengers Genetic Transcription Goals Heart failure Hospitalization Human Hypertension Intake Kidney Knockout Mice Left Ventricular Hypertrophy Link MMP2 gene MMP9 gene Medial Messenger RNA Metalloproteases Mineralocorticoid Receptor Molecular Mus Myocardial Infarction NADPH Oxidase Operative Surgical Procedures Oxidative Stress Pathologic Patients Pharmaceutical Preparations Plasma Prevalence Procedures Role Rupture Ruptured Abdominal Aortic Aneurysm Scheme Smooth Muscle Myocytes Sodium Sodium Chloride Spironolactone Stress Stroke Tamoxifen Testing Time Vascular Diseases Withdrawal Woman abdominal aorta age related alpha Actin clinical practice diagnosis evaluation effective therapy eplerenone insight loss of function male men mortality mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics prevent promoter public health relevance salt intake tempol vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a vascular disease with rising prevalence and a high mortality rate. Current treatment is limited to open or endovascular surgery, a procedure for which only 10% of AAA patients are eligible, highlighting an urgent need for new mechanistic understandings of AAA. With a long term goal to identify new therapeutic targets for AAA, the current proposal will investigate the pathological roles of aldosterone (Aldo), mineralocorticoid receptor (MR), and high salt intake in AAA. Elevated plasma Aldo and high salt intake have been linked to a spectrum of cardiovascular diseases. MR antagonists have been shown to be effective in reducing cardiovascular mortality and hospitalizations for heart failure. However, little is known of the roles of Aldo, MR, and high sal intake in AAA. Recently, the applicants discovered that administration of MR agonists, deoxycorticosterone acetate (DOCA) or Aldo to C57BL/6 male mice induced AAA in the presence of high salt. Importantly, DOCA- or Aldo-salt-induced AAA mimicked human AAA with respect to oxidative stress, vascular inflammation, smooth muscle cell (SMC) degeneration, metalloproteinase (MMP) activation, and elastin degradation. Treatment of mice with spironolactone or eplerenone, two clinically used MR antagonists, effectively attenuated DOC- or Aldo-salt-induced aortic aneurysm formation and rupture. Building on these exciting and novel findings, the applicants further demonstrated that, in isolated mouse aorta, administration of pathological plasma concentrations of Aldo and sodium activated MMP2 and induced oxidative stress, suggesting a direct pathological effect of Aldo and salt on aorta. Interestingly, denuding endothelial cells from isolated aorta had no effect on Aldo-salt-induced MMP2 activation and oxidative stress, indicating that MR in SMC (SMC-MR) is involved. Consistent with this concept, the applicants found that p47phox, a component of NADPH oxidase that has been implicated in human AAA, was markedly upregulated by Aldo-salt in the medial layer of abdominal aortic wall and co-localized with SMC a-Actin, which was completely abolished by treatment of mice with eplerenone. Moreover, treatment of mice with temporal, a free radical scavenger, diminished DOCA-salt-induced AAA. Therefore, the applicants hypothesize that increased plasma Aldo and salt activate SMC-MR and p47phox and thus result in oxidative stress, MMP activation, vascular inflammation, SMC degeneration, and elastin degradation, thereby contributing to AAA. Three specific aims are: 1) test the hypothesis that SMC-MR is required for Aldo-salt-induced AAA; 2) define the mechanism by which SMC-MR targets p47phox to induce AAA; 3) determine whether targeting the Aldo/MR/salt axis is effective for treatment of AAA. To achieve these aims, genetic animal models (SMC- specific MR knockout mice and global p47phox knockout mice) and various molecular, biochemical, and physiopathological approaches will be used. If proposed studies are successful, they will have a profound impact on current basic researches and clinical practices on the etiology, diagnosis, and treatment of AAA.

描述（由申请人提供）：腹主动脉瘤（AAA）是一种患病率不断上升且死亡率很高的血管疾病。目前的治疗仅限于开放或血管内手术，只有 10% 的 AAA 患者符合这种手术条件，这凸显了对 AAA 的新机制理解的迫切需要。长期目标是确定 AAA 的新治疗靶点，目前的提案将研究醛固酮 (Aldo)、盐皮质激素受体 (MR) 和高盐摄入在 AAA 中的病理作用。血浆阿尔多升高和高盐摄入量与一系列心血管疾病有关。 MR 拮抗剂已被证明可有效降低心血管死亡率和心力衰竭住院率。然而，人们对 Aldo、MR 和高盐摄入量在 AAA 中的作用知之甚少。最近，申请人发现向C57BL/6雄性小鼠施用MR激动剂、醋酸脱氧皮质酮(DOCA)或Aldo在高盐存在下诱导AAA。重要的是，DOCA 或醛糖盐诱导的 AAA 在氧化应激、血管炎症、平滑肌细胞 (SMC) 变性、金属蛋白酶 (MMP) 激活和弹性蛋白降解方面模仿了人类 AAA。用螺内酯或依普利酮（两种临床使用的 MR 拮抗剂）治疗小鼠，可有效减弱 DOC 或醛酸盐诱导的主动脉瘤形成和破裂。基于这些令人兴奋的新颖发现，申请人进一步证明，在离体小鼠主动脉中，施用病理血浆浓度的Aldo和钠激活MMP2并诱导氧化应激，表明Aldo和盐对主动脉的直接病理作用。有趣的是，从分离的主动脉中剥离内皮细胞对醛糖盐诱导的 MMP2 活化和氧化应激没有影响，表明 SMC 中的 MR (SMC-MR) 参与其中。与这个概念一致，申请人发现p47phox（与人类AAA有关的NADPH氧化酶的一种成分）在腹主动脉壁内侧层中被Aldo盐显着上调，并且与SMC a-肌动蛋白共定位，这通过用依普利酮治疗小鼠，这种现象被完全消除。此外，用自由基清除剂颞叶治疗小鼠，可以减少 DOCA 盐诱导的 AAA。因此，申请人假设增加的血浆Aldo和盐激活SMC-MR和p47phox，从而导致氧化应激、MMP激活、血管炎症、SMC变性和弹性蛋白降解，从而导致AAA。三个具体目标是：1）检验 SMC-MR 是醛糖盐诱导 AAA 所必需的假设； 2) 明确SMC-MR靶向p47phox诱导AAA的机制； 3) 确定靶向Aldo/MR/盐轴对于治疗AAA是否有效。为了实现这些目标，将使用遗传动物模型（SMC特异性MR敲除小鼠和全局p47phox敲除小鼠）以及各种分子、生化和病理生理学方法。如果拟议的研究成功，将对当前AAA的病因、诊断和治疗的基础研究和临床实践产生深远的影响。