New Therapy via Targeting Androgen Receptor in Monocytes/Macrophages to Battle Atherosclerosis

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The male sex has a higher risk to develop coronary artery diseases, including atherosclerosis. The androgen receptor (AR) is expressed in several atherosclerosis-associated cell types, including monocytes/macrophages, endothelial cells (ECs), and smooth muscle cells (SMCs), but its pathophysiological role in each cell type during the development of atherosclerotic lesions remains unclear. Using the Cre-loxP system, we selectively knocked out AR in these 3 cell types and the resultant AR knockout (ARKO) mice, monocyte/macrophage ARKO, EC-ARKO, and SMC-ARKO, were then crossed with the low-density lipoprotein receptor (LDLR) deficient (LDLR−/−) mice to develop monocyte/macrophage ARKO-LDLR−/−, EC-ARKO-LDLR−/−, and SMC-ARKO-LDLR−/− mice for the study of atherosclerosis. The results showed that the monocyte/macrophage ARKO-LDLR−/− mice had reduced atherosclerosis compared with the wild-type-LDLR−/− control mice. However, no significant difference was detected in EC-ARKO-LDLR−/− and SMC-ARKO-LDLR−/− mice compared with wild-type-LDLR−/− mice, suggesting that the AR in monocytes/macrophages, and not in ECs and SMCs, plays a major role to promote atherosclerosis. Molecular mechanism dissection suggested that AR in monocytes/macrophages upregulated the tumor necrosis factor-α, integrin β2, and lectin-type oxidized LDL receptor 1 molecules that are involved in 3 major inflammation-related processes in atherosclerosis, including monocytes/macrophages migration and adhesion to human umbilical vein ECs, and subsequent foam cell formation. Targeting AR via the AR degradation enhancer, ASC-J9, in wild-type-LDLR−/− mice showed similar effects as seen in monocyte/macrophage ARKO-LDLR−/− mice with little influence on lipid profile. In conclusion, the AR in monocytes/macrophages plays key roles in atherosclerosis and targeting AR with ASC-J9 may represent a new potential therapeutic approach to battle atherosclerosis.

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