Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report. Issue 7 (July 2018)

• Record Type: Journal Article
• Authors: Wilhelmson, Anna S.; Lantero Rodriguez, Marta; Svedlund Eriksson, Elin; Johansson, Inger; Fogelstrand, Per; Stubelius, Alexandra; Lindgren, Susanne; Fagman, Johan B.; Hansson, Göran K.; Carlsten, Hans; Karlsson, Mikael C.I.; Ekwall, Olov; Tivesten, Åsa
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 38:Issue 7(2018)
• Publication Date: 2018-07
• Subjects: androgens -- atherosclerosis -- risk factors -- T-lymphocytes -- thymus gland; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.118.311252
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Objective—: Androgen deprivation therapy has been associated with increased cardiovascular risk in men. Experimental studies support that testosterone protects against atherosclerosis, but the target cell remains unclear. T cells are important modulators of atherosclerosis, and deficiency of testosterone or its receptor, the AR (androgen receptor), induces a prominent increase in thymus size. Here, we tested the hypothesis that atherosclerosis induced by testosterone deficiency in male mice is T-cell dependent. Further, given the important role of the thymic epithelium for T-cell homeostasis and development, we hypothesized that depletion of the AR in thymic epithelial cells will result in increased atherosclerosis. Approach and Results—: Prepubertal castration of male atherosclerosis-prone apoE −/− mice increased atherosclerotic lesion area. Depletion of T cells using an anti-CD3 antibody abolished castration-induced atherogenesis, demonstrating a role of T cells. Male mice with depletion of the AR specifically in epithelial cells (E-ARKO [epithelial cell-specific AR knockout] mice) showed increased thymus weight, comparable with that of castrated mice. E-ARKO mice on an apoE −/− background displayed significantly increased atherosclerosis and increased infiltration of T cells in the vascular adventitia, supporting a T-cell–driven mechanism. Consistent with a role of the thymus, E-ARKO apoE −/− males subjected to prepubertal thymectomy showed no atherosclerosis phenotype. Conclusions—: We show that atherogenesis induced by testosterone/AR deficiency is thymus- and T-cell dependent in male mice and that the thymic epithelial cell is a likely target cell for the antiatherogenic actions of testosterone. These insights may pave the way for new therapeutic strategies for safer endocrine treatment of prostate cancer. Abstract : Supplemental Digital Content is available in the text.