| Autor: |
Mu X; Departments of Pharmacology and Nutritional Sciences., Liu S; Physiology, and., Wang Z; Departments of Pharmacology and Nutritional Sciences., Jiang K; Physiology, and., McClintock T; Physiology, and., Stromberg AJ; Statistics, University of Kentucky, Lexington, Kentucky, USA., Tezanos AV; Statistics, University of Kentucky, Lexington, Kentucky, USA., Lee ES; Department of Research, Sacramento Veterans Affairs Medical Center, Mather, California, USA., Curci JA; Department of Vascular Surgery, Vanderbilt University, Nashville, Tennessee, USA., Gong MC; Physiology, and.; Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, USA., Guo Z; Departments of Pharmacology and Nutritional Sciences.; Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, USA.; Department of Research, Lexington Veterans Affairs Medical Center, Lexington, Kentucky, USA. |
| Abstrakt: |
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. |
