Mineralocorticoid receptor and abdominal aortic aneurysm

描述（申请人提供）：腹主动脉瘤（AAA）是一种发病率上升、死亡率高的血管性疾病。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的新机制理解的迫切需要。为了确定AAA的新治疗靶点，目前的提案将研究醛固酮（Aldo）、矿化皮质激素受体（MR）、血浆Aldo升高和高盐摄入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率方面有效。然而，对Aldo、MR和高盐摄入在AAA中的作用知之甚少。最近，申请人发现MR激动剂、醋酸去氧皮质酮（DOCA）或Aldo对C57BL/6雄性小鼠在高盐存在下诱导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模拟了人类AAA。用两种临床使用的MR拮抗剂螺内酯或依普利酮治疗小鼠，可有效减轻DOC或aldo盐诱导的主动脉瘤形成和破裂。在这些令人兴奋的新发现的基础上，申请人进一步证明，在离体小鼠主动脉中，病理血浆浓度的Aldo和钠激活MMP2并诱导氧化应激，这表明Aldo和盐对主动脉有直接的病理作用。有趣的是,

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.