title: RORα suppresses proliferation of vascular smooth muscle cells through activation of AMP-activated protein kinase.
abstract: BACKGROUND
  Retinoic acid-related orphan receptor α (RORα) has been implicated in the progression of atherosclerosis, but its role in the proliferation of vascular smooth muscle cells (vSMCs) has not been fully examined. We previously reported that RORα activates AMP-activated protein kinase (AMPK), which is associated with the suppression of vSMC proliferation. Therefore, we investigated the suppressive function of RORα on the proliferation of vSMCs and the molecular mechanisms involved.
  
  
  RESULTS
  First, RORα and its activator, cholesterol sulfate (CS), induced the activation of AMPK in both human aortic SMCs and rat A7r5 cells, which was accompanied by the suppression of mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase 1. Second, RORα and CS modulated the expression of cell-cycle-regulating factors, such as p53, p27, and cyclin D in vSMCs. Consistent with this, the overexpression of RORα or CS treatment suppressed the proliferation of human aortic SMCs and rat A7r5 cells, possibly through G1 arrest. RORα and CS also inhibited the migration of A7r5 cells in two-dimensional and three-dimensional cell migration assays. Finally, we demonstrated that the infusion of adenovirus encoding RORα into arteries suppressed neointima formation after balloon injury in rats.
  
  
  CONCLUSIONS
  These results demonstrate that RORα inhibits vSMC proliferation through AMPK-induced mTOR suppression, and suggest that RORα is a therapeutic target for the cardiovascular diseases associated with vSMC proliferation.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea; Bio-MAX Institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: World Class University Program, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea; Bio-MAX Institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Han
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea; Bio-MAX Institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Hyeon-Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: World Class University Program, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea; Bio-MAX Institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea. Electronic address: molee@snu.ac.kr.
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Atherosclerosis; RORα; vSMC proliferation