The role of androgen receptors in atherosclerosis

Abstract

Male disadvantage in cardiovascular health is well recognised. However, the influence of androgens on atherosclerosis, one of the major causes of many life-threatening cardiovascular events, is not well understood. With the dramatic increase in clinical prescription of testosterone in the past decade, concerns about the cardiovascular side-effects of androgen supplementation or androgen deprivation therapy are increasing. Potential atheroprotective effects of testosterone could be secondary to (aromatase-mediated) conversion into oestradiol or, alternatively, to direct activation of androgen receptors (AR). Recent development of animal models with cell-specific AR knockout has indicated a complex role for androgen action in atherosclerosis. Most studies suggest androgens are atheroprotective but the precise role of AR remains unclear. Increased use of AR knockout models should clarify the role of AR in atherogenesis and, thus, lead to exploitation of this pathway as a therapeutic target.

Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies

“…AR-KO and castration accelerated atherosclerosis in apolipoprotein E-deficient background [112], whereas in mice lacking a receptor for LDL, macrophage-specific AR-KO reduced atheromatous lesions [113]. These results suggest that androgens directly affect the cardiac muscle cells, as well as the vascular endothelial and smooth muscle cells, and thus have an effect on CV disease without affecting energy metabolism [114]. This review focuses on rodent studies of the effects of androgen ablation on energy metabolism, including body composition and T2DM, because these were involved in CV risk and are evident and important in the clinical and epidemiological studies described above.…”

Loss of Estrogen-Related Receptor Alpha Facilitates Angiogenesis in Endothelial Cells

“…For example, estrogen receptors are involved in angiogenesis, vascular tone, and atheroprotection in endothelial and/or vascular smooth-muscle cells (17)(18)(19)(20)(21)(22). Progesterone receptors are negative regulators of angiogenesis, whereas androgen receptors promote ischemic reperfusion and are atheroprotective (23)(24)(25)(26)(27). Glucocorticoids and mineralocorticoids regulate vascular tone and negatively regulate angiogenesis by acting on vascular smooth-muscle cells and ECs (28)(29)(30)(31).…”

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

“… 14 A crucial step for the design of selective AR modulators with a beneficial cardiovascular profile will be the identification of the target cell(s) for the cardiovascular actions of testosterone. The target cell and mechanism through which androgens/AR protect against atherosclerosis remains unclear 15 ; recent studies using cell-specific depletion of the AR do not support endothelial or vascular smooth muscle cells as targets for the antiatherogenic actions of testosterone. 16 Further, contrary to the effects of castration or whole-body AR depletion, 4 monocyte/macrophage-specific AR knockout reduces atherosclerosis.…”