Mineralocorticoid receptor and abdominal aortic aneurysm

盐皮质激素受体与腹主动脉瘤

• 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
• 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

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（由申请方提供）：腹主动脉瘤（AAA）是一种患病率和死亡率不断上升的血管疾病。目前的治疗仅限于开放或血管内手术，只有10%的AAA患者符合条件，这突出了对AAA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Aldo升高和高盐摄入与一系列心血管疾病有关。已证明MR拮抗剂可有效降低心血管死亡率和心力衰竭住院率。然而，很少有人知道的奥尔多，MR和高盐摄入量在AAA中的作用。最近，申请人发现，在高盐存在下，向C57 BL/6雄性小鼠施用MR激动剂、醋酸脱氧皮质酮（DOCA）或Aldo诱导AAA。重要的是，DOCA或醛盐诱导的AAA在氧化应激、血管炎症、平滑肌细胞（SMC）变性、金属蛋白酶（MMP）活化和弹性蛋白降解方面模仿人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或醛盐诱导的主动脉瘤形成和破裂。基于这些令人兴奋和新颖的发现，申请人进一步证明，在分离的小鼠主动脉中，施用病理血浆浓度的Aldo和钠活化MMP 2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， 剥脱离体主动脉内皮细胞对醛盐诱导的MMP 2活化和氧化应激没有影响，表明SMC中的MR（SMC-MR）参与其中。与该概念一致，申请人发现p47 phox（与人AAA有关的NADPH氧化酶的组分）在腹主动脉壁的中间层中被醛盐显著上调，并与SMC α-肌动蛋白共定位，其通过用依普利酮处理小鼠而完全消除。此外，用自由基清除剂temporal治疗小鼠，减少了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p47 phox，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，从而促成AAA。三个具体目标是：1）检验SMC-MR是醛盐诱导的AAA所必需的假设; 2）定义SMC-MR靶向p47 phox诱导AAA的机制; 3）确定靶向Aldo/MR/盐轴是否有效治疗AAA。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p47 phox敲除小鼠）和各种分子、生物化学和生理病理学方法。如果研究成功，将对AAA的病因、诊断和治疗的基础研究和临床实践产生深远影响。