Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and fatality rate in men than women. However, the mechanism by which androgen mediates aortic aneurysms is largely unknown. Herein, we found that male mice, not female mice, developed aortic aneurysms when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (AR) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and aortic aneurysms. We demonstrated that administration of anti-PD-1 Ab and adoptive PD-1 deficient T cell transfer reinstated Aldo-salt-induced aortic aneurysms in orchiectomized mice, and genetic deletion of PD-1 exacerbated aortic aneurysms induced by high-fat diet and angiotensin II (Ang II) in non-orchiectomized mice. Mechanistically, we discovered that AR bound to the PD-1 promoter to suppress its expression in the spleen. Thus, our study unveils a mechanism by which androgen aggravates aortic aneurysms by suppressing PD-1 expression in T cells. Moreover, our study suggests that some cancer patients might benefit from screenings for aortic aneurysms during immune checkpoint therapy.

Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.