Monday, May 6, 2024
5/6/2024
Project Summary Abdominal aortic aneurysm (AAA) is a severe vascular disease affecting millions of Americans with high morality. Currently, no medication has been approved to treat this devastating disease. Women are less and later to develop AAA than men. Nevertheless, AAA in women is more aggressive. It grows faster. It is more likely to rupture at smaller diameters, resulting in higher mortality, with worse morbidity after surgical repair. Smoking promotes AAA in both men and women, but women who smoke are at higher risk for AAA than men. Estrogen (E2) has long been believed to protect premenopausal women from AAA. However, its effect on AAA in animal models and human clinical trials is controversial. Several AAA animal models have been developed and have contributed to our current understating of AAA. However, one of the common limitations of these animal models is to use young animals to study AAA, which occurs mainly in older people. To fill this significant gap, we developed a relatively new AAA mouse model that requires using older male mice, activation of mineralocorticoid receptor (MR) by aldosterone (Aldo), and high salt intake to induce AAA. Surprisingly, we found that Aldo and salt (Aldo-salt) only induced AAA in male mice but not in female mice unless female mice were subjected to ovariectomy (Ovx) or nicotine. Mechanistically, MR was upregulated by Aldo-salt with Ovx or nicotine in endothelial cells (EC) in the aorta with accumulation in the nucleus, indicating E2 may protect female mice from AAA via suppressing MR expression and/or nuclear translocation in EC in the aorta. Interestingly, Per2, a core circadian gene, interacts with ER¿ and MR and is required for E2 to suppress MR expression. Moreover, genetic deletion of MR in EC, but not smooth muscle cell and myeloid cells, inhibited Aldo-salt-induced AAA, concordant with a reduction in ICAM1 upregulation in EC and neutrophil (N¿) infiltration in the aorta. Based on the literature and robust evidence from our preliminary data, we hypothesize that E2 inhibits Aldo-salt-induced MR protein upregulation and nuclear translocation via ER¿/Per2/MR interaction in EC in the aorta, thus protecting female mice from ICAM1 upregulation, Nf infiltration, and aortic aneurysm. Aim 1 is to define the mechanism by which E2 protects Aldo-salt-induced aortic aneurysm by inhibiting MR protein upregulation and nuclear translocation via ER¿ in EC in the aorta in female mice with Ovx and nicotine; Aim 2 is to determine whether targeting the Per2/MR/ICAM1/Nf signaling can protect female mice with Ovx or nicotine from Aldo-salt-induced aortic aneurysm. To achieve these goals, 12-week-old or 12- month-old C57BL/6, iECER¿KO, Per2KO, iECPer2KO, iECMRKO, and WT control female mice will be subjected to Ovx or nicotine and then treated with E2/progesterone (P4)/dihydrotestosterone (DHT)/ICAM1/ Ly6G antibody (Ab). The effect of hormone therapy, genetic deletion, and Ab blocking on aging/Aldo-salt- induced AAA will be determined. The proposed studies will shed new mechanistic insight into the pathologies of AAA in women and provide preclinical evidence to help identify new therapeutic targets against AAA.
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