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Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report
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 testost...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039408/ https://www.ncbi.nlm.nih.gov/pubmed/29853568 http://dx.doi.org/10.1161/ATVBAHA.118.311252 |
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author | 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 |
author_facet | 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 |
author_sort | Wilhelmson, Anna S. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6039408 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-60394082018-07-20 Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report 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 Arterioscler Thromb Vasc Biol Basic Sciences 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. Lippincott Williams & Wilkins 2018-07 2018-04-05 /pmc/articles/PMC6039408/ /pubmed/29853568 http://dx.doi.org/10.1161/ATVBAHA.118.311252 Text en © 2018 American Heart Association, Inc. |
spellingShingle | Basic Sciences 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 Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report |
title | Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report |
title_full | Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report |
title_fullStr | Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report |
title_full_unstemmed | Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report |
title_short | Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report |
title_sort | testosterone protects against atherosclerosis in male mice by targeting thymic epithelial cells—brief report |
topic | Basic Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039408/ https://www.ncbi.nlm.nih.gov/pubmed/29853568 http://dx.doi.org/10.1161/ATVBAHA.118.311252 |
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