title: New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis.
abstract: 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.
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Ave, Box 626, Rochester, NY 14642. chang@urmc.rochester.edu or Lin Wang, Chawnshang Chang Sex Hormone Research Center, The Kidney and Blood Purification Center, Tianjin Institute of Urology, Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin, China 300211. E-mail wang.lin@medmail.com.cn.
authors.forename: Chiung-Kuei
authors.initials: CK
authors.lastname: Huang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Pang
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Niu
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.forename: Janet D
authors.initials: JD
authors.lastname: Sparks
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D015153:Blotting, Western; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D059305:Diet, High-Fat; D005487:Foam Cells / Q000166:cytology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000172:deficiency* / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D003474:Curcumin; D011944:Receptors, Androgen; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; C471106:ASC-J9 compound
keywords: androgen; atherosclerosis; macrophages; receptors, androgen