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

Journal article
Authors Anna S K Wilhelmson
Marta Lantero Rodriguez
Elin Svedlund Eriksson
Inger Johansson
Per Fogelstrand
Alexandra Stubelius
Susanne Lindgren
Johan Bourghardt Fagman
Göran K Hansson
Hans Carlsten
Mikael C I Karlsson
Olov Ekwall
Åsa Tivesten
Published in Arteriosclerosis, thrombosis, and vascular biology
Volume 38
Issue 7
Pages 1519-1527
ISSN 1524-4636
Publication year 2018
Published at Wallenberg Laboratory
Institute of Clinical Sciences, Department of Surgery
Institute of Medicine, Department of Rheumatology and Inflammation Research
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Institute of Clinical Sciences, Department of Pediatrics
Pages 1519-1527
Language en
Links dx.doi.org/10.1161/ATVBAHA.118.3112...
www.ncbi.nlm.nih.gov/entrez/query.f...
https://gup.ub.gu.se/file/207575
Subject categories Immunology in the medical area

Abstract

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.

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