Androgen aggravates aortic aneurysms via suppression of PD-1 in mice
Xufang Mu, Shu Liu, Zhuoran Wang, Kai Jiang, Tim McClintock, Arnold J. Stromberg, Alejandro V. Tezanos, Eugene S. Lee, John A. Curci, Ming C. Gong, Zhenheng Guo
Xufang Mu, Shu Liu, Zhuoran Wang, Kai Jiang, Tim McClintock, Arnold J. Stromberg, Alejandro V. Tezanos, Eugene S. Lee, John A. Curci, Ming C. Gong, Zhenheng Guo
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Research Article Inflammation Vascular biology

Androgen aggravates aortic aneurysms via suppression of PD-1 in mice

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.

Authors

Xufang Mu, Shu Liu, Zhuoran Wang, Kai Jiang, Tim McClintock, Arnold J. Stromberg, Alejandro V. Tezanos, Eugene S. Lee, John A. Curci, Ming C. Gong, Zhenheng Guo

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Figure 9

Androgen suppresses PD-1 mRNA and protein expression in the spleen in mice administered Aldo-salt.

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Androgen suppresses PD-1 mRNA and protein expression in the spleen in mi...
(A−D) Representative immunostainings and quantitative data for PD-1 protein expression in spleens from 10-month-old male C57BL/6J mice with orchiectomy or sham operation 10 days after Aldo-salt administration (n = 3–4/group) or from orchiectomized mice 4 weeks after Aldo-salt administration with and without DHT pellet implantation (n = 3/group). Percentage of areas fraction = (PD-1+ area/area of fields of view) × 100%. The data were calculated from 5 fields of view randomly photographed per splenic section per mouse. (E−H) Representative Western blots and quantitative data for PD-1, CD3ε, CD19, and GAPDH protein expression in spleens from 10-month-old male mice with orchiectomy or sham operation 10 days after Aldo-salt administration (n = 5/group). (I) Pdcd1 (the gene encodes PD-1) mRNA expression was normalized to 36B4 (a housekeeping gene, also called Rplp0 [ribosomal protein lateral stalk subunit P0]) in spleens from 10-month-old male mice with orchiectomy or sham operation 10 days after Aldo-salt administration (n = 13/group). (J) Schematic diagram of the 12 AREs in the 5 kb mouse PD-1 promoter. ATG, translation start codon. ChIP-F, ChIP PCR forward primers; ChIP-R, ChIP PCR reverse primers. (K−M) Representative and quantitative ChIP-PCR data for the control Ab, anti-AR Ab 1, and anti-AR Ab 2 in the spleen (n = 3/group). NTC, no template control. (N and O) AR expression in HEK293 cells suppressed PD-1 promoter activity (n = 4/group). Data are expressed as the mean ± SEM and were analyzed by 2-tailed, unpaired t test (B, D, F−H, I, L, and M) and 1-way ANOVA with multiple-comparison test (O). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Scale bars: 20 μm and 100 μm (enlarged insets).