New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis

Hypertension. 2014 Jun;63(6):1345-53. doi: 10.1161/HYPERTENSIONAHA.113.02804. Epub 2014 Mar 31.

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.

Keywords: androgen; atherosclerosis; macrophages; receptors, androgen.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / prevention & control
  • Blotting, Western
  • CD18 Antigens / metabolism
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cells, Cultured
  • Curcumin / analogs & derivatives
  • Curcumin / pharmacology
  • Diet, High-Fat
  • Foam Cells / cytology
  • Human Umbilical Vein Endothelial Cells / cytology
  • Humans
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Monocytes / cytology
  • Monocytes / metabolism*
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Receptors, Androgen / deficiency*
  • Receptors, Androgen / genetics
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one
  • CD18 Antigens
  • Receptors, Androgen
  • Receptors, LDL
  • Tumor Necrosis Factor-alpha
  • Curcumin