Mineralocorticoid receptor and abdominal aortic aneurysm

Aortic aneurysm is a life-threatening vascular disease with rising prevalence and a high mortality rate. The current therapy is limited to surgery, highlighting the urgent need to understand the underlying mechanisms in order to develop effective non-surgical therapeutics. With a long term goal to identify new therapeutic targets for aortic aneurysm, the current proposal focuses on the effect of aldosterone (Aldo), mineralocorticoid receptor (MR), and high salt intake on their previously unrecognized but potentially highly significant roles in aortic aneurysm. Elevated plasma Aldo concentrations and high salt intake have been linked to a spectrum of cardiovascular diseases, including hypertension, stroke, myocardial infarction, left ventricular hypertrophy, and heart failure. MR antagonists provide additional benefits in patients with heart failure. However, little is known whether or not Aldo/MR and high salt intake play a role in aortic aneurysm. We recently reported that administration of deoxycorticosterone acetate (DOCA) and salt or Aldo and salt, but not DOCA or salt alone, to C57BL/6 male mice induced aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or Aldo and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to oxidative stress, vascular inflammation, smooth muscle cell (SMC) degeneration, metalloproteinase (MMP) activation, and elastin degradation. Spironolactone or eplerenone, two clinically used MR antagonists, significantly attenuated DOCA and salt- or Aldo and salt-induced aortic aneurysm. Build on these novel findings, we further investigated the mechanisms underlying Aldo and salt-induced aortic aneurysm. We demonstrated that, in isolated mouse aorta, administration of pathological plasma concentrations of Aldo and sodium activated MMP2 and induced oxidative stress. Importantly, denuding endothelial cells from isolated aorta had no effect on Aldo-salt-induced MMP2 activation and oxidative stress, suggesting that MR in SMC (SMC-MR) is involved. Consistent with this concept, we found that p47phox, a component of NADPH oxidase, was markedly upregulated by Aldo-salt in the medial layer of abdominal aortic wall and co-localized with SMC Ą-Actin. We found that 47phox mRNA was also up-regulated by DOCA-salt in abdominal aorta in mice, MR bound to the p47phox promoter, and Aldo significantly stimulated p47phox promoter activity in cultured SMC. Moreover, treatment of mice with temporal, a membrane-permeable free radical scavenger, diminished DOCA-saltinduced aortic aneurysm and treatment of mice with eplerenone abolished Aldo-salt-induced p47phox upregulation. Taken together, these results suggest that Aldo/MR and high salt are important new players in aortic aneurysm and targeting Aldo/MR and high salt may represent a new therapeutic strategy to prevent and treat aortic aneurysm. Therefore, we hypothesize that increased plasma Aldo and salt coordinately activate SMC-MR and p47phox thus result in oxidative stress, MMP activation, vascular inflammation, SMC degeneration, and elastin degradation, and thereby contributes to aortic aneurysm. If proposed studies are successful, they will have a profound impact on current basic researches and clinical practices about the etiology, clinic diagnosis, evaluation, and treatment of aortic aneurysm. Aim 1 РTest the hypothesis that SMC-MR is required for Aldo-salt-induced aortic aneurysm. A tamoxifen inducible SMC-specific MR knockout mouse model will be used to investigate the loss of function of SMC-MR in Aldo-salt-induced oxidative stress, MMP activation, vascular inflammation, SMC degeneration, elastin degradation, and aortic aneurysm formation Aim 2 РDefine the mechanism by which SMC-MR targets p47phox to induce aortic aneurysm. A tamoxifen inducible SMC-specific MR knockout mouse model and a global p47phox knockout mouse model will be used to examine how P47phox is transcriptionally upregulated by Aldo-salt and whether p47phox is critical for Aldo-salt-induced aortic aneurysm. Aim 3 РDetermine whether targeting the Aldo/MR/salt axis is effective for treatment of aortic aneurysm. Three distinct strategies РMR antagonist, SMC-specific MR knockout, and withdrawal from high salt intake will be applied after the onset of Aldo-salt-induced aortic dilation and the effects on aortic aneurysm progression will be examined.