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

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

展开

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）是一种血管疾病，患病率上升且死亡率较高。当前的治疗仅限于开放或血管内手术，该手术只有10％的AAA患者符合条件，强调迫切需要对AAA的新机械理解。有了一个长期目标，可以识别AAA的新治疗靶标，目前的提案将研究AAA中醛固酮（ALDO），矿物皮质激素受体（MR）和高盐摄入量的病理作用。升高的血浆Aldo和高盐摄入量已与一系列心血管疾病有关。 MR拮抗剂已被证明可以有效地降低心血管死亡率和心力衰竭住院治疗。但是，对于AAA中Aldo，MR和High Sal摄入量的作用知之甚少。最近，申请人发现，在高盐存在下，施用MR激动剂，乙酸脱氧核苷（DOCA）或ALDO对C57BL/6雄性小鼠的给药会诱导AAA。重要的是，关于氧化应激，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，模仿了人类AAA的DOCA-或ALDO诱导的AAA AAA。用螺内酯或eplerenone治疗小鼠，两名临床使用的MR拮抗剂有效地减弱了DOC或Aldo-salt诱导的主动脉瘤形成和破裂。在这些令人兴奋和新颖的发现的基础上，申请人进一步证明，在孤立的小鼠主动脉中，Aldo和钠激活的MMP2的病理血浆浓度给药并诱导氧化应激，这表明Aldo和盐对主动脉的直接病理作用。有趣的是，来自分离的主动脉的剥离内皮细胞对Aldo-盐诱导的MMP2激活和氧化应激没有影响，表明SMC（SMC-MR）中的MR涉及。与这个概念一致的是，申请人发现，p47phox是与人AAA有关的NADPH氧化酶的一个成分，在腹主动脉壁的内侧层中明显上调，并与SMC A-Atacin共定位，并通过与ePleNeNone的鼠标进行了完全消除。此外，用颞叶治疗小鼠，自由基的清道夫，减少了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退化和弹性蛋白降解，从而对AAA有助于AAA。三个具体目的是：1）检验以下假设：Aldo-Salt诱导的AAA需要SMC-MR； 2）定义SMC-MR靶向P47phox诱导AAA的机制； 3）确定靶向Aldo/MR/盐轴是否有效治疗AAA。为了实现这些目的，将使用遗传动物模型（SMC-特定于MR敲除小鼠和全球P47Phox敲除小鼠）以及各种分子，生化和生理病理学方法。如果提出的研究成功，它们将对当前的基础研究和临床实践产生深远的影响，对AAA的病因，诊断和治疗。