Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells

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.

Prepubertal castration of male atherosclerosis-prone apoE-/- mice increased atherosclerotic lesion area. Depletion of T cells using an anti-CD (cluster of differentiation) 3 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.

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.

Arteriosclerosis, thrombosis, and vascular biology. 2018 May 31 [Epub ahead of print]

Anna S Wilhelmson, Marta Lantero Rodriguez, Elin Svedlund Eriksson, Inger Johansson, Per Fogelstrand, Alexandra Stubelius, Susanne Lindgren, Johan B Fagman, Göran K Hansson, Hans Carlsten, Mikael C I Karlsson, Olov Ekwall, Åsa Tivesten

From the Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine (A.S.W., M.L.R., E.S.E., I.J., P.F., J.B.F., A.T.)., Center for Bone and Arthritis Research, Institute of Medicine (A.S., H.C.)., Department of Rheumatology and Inflammation Research, Institute of Medicine (A.S., S.L., H.C., O.E.)., University of Gothenburg, Sweden; and Department of Medicine, Center for Molecular Medicine (G.K.H.)., Department of Microbiology, Tumor, and Cell Biology (M.C.I.K.), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden., From the Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine (A.S.W., M.L.R., E.S.E., I.J., P.F., J.B.F., A.T.) .

E-Newsletters

Newsletter subscription

Free Daily and Weekly newsletters offered by content of interest

The fields of GU Oncology and Urology are rapidly advancing. Sign up today for articles, videos, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.

Subscribe