A Novel Mechanism by which Smooth Muscle BMAL1 Regulates IL-6 and Sexual Dimorphism of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a vascular disease affecting millions of Americans and accounts for 15,000 deaths per year in the United States. Currently, open or endovascular surgery is the only therapeutic option for aortic aneurysm and no drug has been approved for the treatment of this devastating disease, 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 a novel mechanism by which sexual dimorphism of AAA is regulated by BMAL1/IL6 signaling in animal models. Elevated plasma aldosterone (Aldo) and high salt intake have been linked to a spectrum of cardiovascular diseases, including hypertension, stroke, myocardial infarction, left ventricular hypertrophy, and heart failure. However, little is known of the roles of Aldo and salt in AAA. We recently reported that administration of mineralocorticoid receptor (MR) agonists, deoxycorticosterone acetate (DOCA) or Aldo plus salt, but not Aldo, DOCA or salt alone, to C57BL/6 male mice potently induces AAA. While the mechanism remains elusive, our preliminary data show that Aldo-salt-induced AAA only occurred in male mice but not in female mice and orchidectomized (orx) male mice. A similar finding was also found in the angiotensin II (Ang II)-salt AAA mouse model. We are excited about these findings as these findings not only demonstrated Aldo- or Ang II-salt-induced AAA recapitulates sexual dimorphism (AAA is more common in men than in women) of human AAA but indicate that sexual hormone may play a critical role in Aldo- or Ang II-salt-induced AAA. In our effort to investigate the mechanism that underlies sexual dimorphism of AAA, our preliminary data identified several genes that are implicated in vascular inflammation, oxidative stress, and circadian rhythm were selectively upregulated by Aldo-salt in aorta in male mice but not in female mice and orx male mice. Among these genes, BMAL1 and interleukin 6 (IL-6) are most interesting because BMAL1 has not been reported to be implicated in AAA despite that it has long recognized that aortic dissection and rupture are characterized by circadian variation, and because recent large GWAS studies implicated IL-6 signaling in human AAA but whether IL-6 causes AAA is largely unknown. Consistent with their roles in human AAA, our preliminary data show that selective deletion of Bmal1 from smooth muscle abolished Aldo- or DOCA-salt-induced IL-6 upregulation in aorta and AAA, and treatment of mice with a novel small molecule inhibitor targeting the IL-6 signaling largely diminished Aldo-salt-induced AAA. Based upon our preliminary data and literatures that testosterone (T) promotes whereas estrogen (E2) protects animals from AAA, we hypothesize that sexual dimorphism in Aldo- or Ang II-salt-induced AAA is critically regulated by T and E2 via SM-BMAL1 and IL-6 signaling, and targeting IL-6 signaling as a novel threptic strategy against Aldo- or Ang II-salt-induced AAA.