Mineralocorticoid receptor and abdominal aortic aneurysm

盐皮质激素受体与腹主动脉瘤

• 批准号: 8792925
• 负责人: MING C GONG
• 金额: $ 53.15万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 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/8792925
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Accounting; Acetates; Actins; Affect; Age; Agonist; Aldosterone; Aldosterone Antagonists; Animal Model; Aorta; Aortic Aneurysm; Attenuated; Basic Science; Binding; Biochemical; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinic; Country; Deoxycorticosterone; Diagnosis; Disease; Elastin; Endothelial Cells; Etiology; Free Radical Scavengers; Genetic; Goals; Heart failure; Hospitalization; Human; Hypertension; Intake; Kidney; Knockout Mice; Left Ventricular Hypertrophy; Link; MMP2 gene; MMP9 gene; Matrix Metalloproteinases; Medial; Membrane; Messenger RNA; Metalloproteases; Mineralocorticoid Receptor; Molecular; Mus; Myocardial Infarction; NADPH Oxidase; Operative Surgical Procedures; Oxidative Stress; 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; clinical practice; diagnosis evaluation; effective therapy; eplerenone; insight; loss of function; male; men; mortality; mouse model; new therapeutic target; novel; novel therapeutics; prevent; promoter; public health relevance; salt intake; tempol; vascular inflammation

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(申请人提供)：腹主动脉瘤(AAA)是一种发病率上升和死亡率高的血管疾病。目前的治疗仅限于开放或血管内手术，只有10%的AAA患者有资格接受这种手术，这突显出迫切需要对AAA有新的机制理解。为了长期寻找治疗AAA的新靶点，目前的建议将调查醛固酮(ALDO)、盐皮质激素受体(MR)和高盐摄入在AAA中的病理作用。血浆Aldo升高和高盐摄入量与一系列心血管疾病有关。MR拮抗剂已被证明在降低心血管死亡率和心力衰竭住院方面有效。然而，人们对Aldo、MR和高Sal摄入量在AAA中的作用知之甚少。最近，申请人发现，给予MR激动剂、脱氧皮质酮醋酸酯(DOCA)或Aldo给C57BL/6雄性小鼠在高盐存在下可诱导AAA。重要的是，DOCA或Aldo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与人AAA相似。用螺内酯或依普利酮治疗小鼠，这两种临床使用的MR拮抗剂有效地减轻了DOC或Aldo盐诱导的主动脉瘤的形成和破裂。在这些激动人心的新发现的基础上，申请者进一步证明，在分离的小鼠主动脉中，给予病理性血浆浓度的Aldo和钠会激活MMP2并诱导氧化应激，这表明Aldo和盐对主动脉有直接的病理影响。有趣的是， 剥脱主动脉内皮细胞对Aldo盐诱导的MMP2活化和氧化应激无影响，提示SMC的MR(SMC-MR)参与了MMP2的激活和氧化应激。与这一概念一致，申请人发现，在人类AAA中涉及的NADPH氧化酶的一种成分p47Phox，在腹主动脉壁中层被Aldo盐显著上调，并与SMC a-肌动蛋白共同定位，后者可通过依普利酮治疗小鼠而完全取消。此外，用自由基清除剂TIMAL治疗小鼠，可以减少DOCA-盐诱导的AAA。因此，申请人假设增加血浆Aldo和盐会激活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。三个具体的目标是：1)验证AAA需要SMC-MR的假设；2)确定SMC-MR靶向p47Phox诱导AAA的机制；3)确定靶向Aldo/MR/Salt轴是否对AAA有效。为了实现这些目标，将使用遗传动物模型(SMC特异性MR基因敲除小鼠和全球p47Phox基因敲除小鼠)以及各种分子、生化和生理病理学方法。如果建议的研究成功，他们将对目前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。