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.
Abdominal aortic aneurysm (AAA) is defined as a permanent localized dilations of aorta, affect 4 to 8% of men and 0.5 to 1.5% of women over the age of 60, and account for about 2% of all deaths in Western countries. AAA is a vascular disease with rising prevalence and a high mortality rate (65% to 85%) related to AAA rupture. Currently, surgery is the only option for treatment of AAA and no drug has been approved for the treatment of this devastating disease. The goals of this application are to elucidate the mechanisms responsible for AAA and thereby identify new therapeutic targets to develop new drugs to treat AAA.
|Lutshumba, Jenny; Liu, Shu; Zhong, Yu et al. (2018) Deletion of BMAL1 in Smooth Muscle Cells Protects Mice From Abdominal Aortic Aneurysms. Arterioscler Thromb Vasc Biol 38:1063-1075
|Liu, Shu; Gong, Ming C; Guo, Zhenheng (2017) A New Mouse Model for Introduction of Aortic Aneurysm by Implantation of Deoxycorticosterone Acetate Pellets or Aldosterone Infusion in the Presence of High Salt. Methods Mol Biol 1614:155-163