Abstract 588: Androgen Promotes Aortic Aneurysms Via Suppressing PD-1 In Male Mice

Objective: Male sex is a well-established risk factor for abdominal aortic aneurysms but the underlying mechanisms remain to be fully understood. Our lab reported aldosterone and high salt (aldo-salt) induced aortic aneurysms in an age-dependent manner in male mice but whether it shows sex dimorphisms as in human is unknown. The current study tested the hypothesis that male mice are more susceptible to aldo-salt induced aortic aneurysms through androgen mediation and investigated the potential mechanisms. Results: Ten-month-old male and female mice were used in all experiments. We first demonstrated the sex differences in the aldo-salt model with 70% incidence in male mice (7/10) compared to complete protection in female mice (0/9). Next, we showed androgen and androgen receptor (AR) mediated the process by several independent experiments: 1) orchiectomy provided strong protection (13.3%, 2/15) compared to sham control (69.2%, 9/13); 2) Exogenous DHT administration to orchiectomized mice restored the aneurysms formation (55%, 6/11); 3) inhibition of AR function by drug decreased total incidence compared to control (2/11 vs. 7/11). To dissect the mechanism, we conducted bulk RNA sequencing in aortas from 3 groups of mice given aldo-salt 1) intact male mice; 2) orchiectomized mice; and 3) orchiectomized mice with DHT. Through a series of bioinformatic analyses, we found PD-1 signaling pathway was significantly enriched in orchiectomized mice compared to control and reversed by DHT addition. Next, we found a significantly higher expression of PD-1 in spleen from orchiectomized mice than sham mice with aldo-salt presence, at both protein and mRNA levels. Mechanistically we showed AR could bind to PD-1 promoter region and suppressed PD-1 expression. Finally, we injected αPD-1 antibody or control IgG antibody to orchiectomized mice during the aldo-salt administration to confirm phenotypes. Results showed that neutralization of PD-1 partially abolished the orchiectomy protection (0/8 vs. 5/12). Conclusions: Our results demonstrated that male mice are more susceptible to aldosterone and high salt-induced aortic aneurysms. Androgen and its receptor mediate the high susceptibility in male mice partially through PD-1 signaling pathway.