Abstract

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

Document Type

Article

Publication Date

6-2024

Notes/Citation Information

© 2024, Mu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI169085

Funding Information

This work is supported in part by NIH grants HL125228, HL141103, HL142973, HL164398, and HL166225 (to MCG and ZG); VA Merit Award CX001683 (to ESL and ZG); NIH grants R01 DC014468 and K18 DC014050 (to TM); an Institutional Development Award from the US National Institute of General Medical Sciences of the NIH (P30GM127211, to the University of Kentucky Center of Research in Obesity and Cardiovascular Disease); and the Office of the Vice President for Research and NIH National Cancer Insti- tute (NCI) Center Core Support grant P30 CA177558 (to the Uni- versity of Kentucky Markey Cancer Center and Flow Cytometry and Immune Monitoring Core Facility).

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