PMID- 25017905
OWN - NLM
STAT- MEDLINE
DCOM- 20150420
LR  - 20171116
IS  - 1874-1754 (Electronic)
IS  - 0167-5273 (Linking)
VI  - 175
IP  - 3
DP  - 2014 Aug 20
TI  - RORalpha suppresses proliferation of vascular smooth muscle cells through activation 
      of AMP-activated protein kinase.
PG  - 515-21
LID - S0167-5273(14)01110-3 [pii]
LID - 10.1016/j.ijcard.2014.06.043 [doi]
AB  - BACKGROUND: Retinoic acid-related orphan receptor alpha (RORalpha) 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 RORalpha activates AMP-activated protein kinase (AMPK), which is associated with 
      the suppression of vSMC proliferation. Therefore, we investigated the suppressive 
      function of RORalpha on the proliferation of vSMCs and the molecular mechanisms 
      involved. RESULTS: First, RORalpha 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, RORalpha 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 RORalpha or CS treatment 
      suppressed the proliferation of human aortic SMCs and rat A7r5 cells, possibly 
      through G1 arrest. RORalpha 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 RORalpha into arteries 
      suppressed neointima formation after balloon injury in rats. CONCLUSION: These 
      results demonstrate that RORalpha inhibits vSMC proliferation through AMPK-induced 
      mTOR suppression, and suggest that RORalpha is a therapeutic target for the 
      cardiovascular diseases associated with vSMC proliferation.
CI  - Copyright (c) 2014 Elsevier Ireland Ltd. All rights reserved.
FAU - Kim, Eun-Jin
AU  - Kim EJ
AD  - College of Pharmacy, Seoul National University, Seoul, South Korea; Bio-MAX 
      Institute, Research Institute of Pharmaceutical Sciences, Seoul National 
      University, Seoul, South Korea.
FAU - Choi, Young-Keun
AU  - Choi YK
AD  - World Class University Program, Research Institute of Aging and Metabolism, 
      Kyungpook National University School of Medicine, Daegu, South Korea.
FAU - Han, Yong-Hyun
AU  - Han YH
AD  - College of Pharmacy, Seoul National University, Seoul, South Korea; Bio-MAX 
      Institute, Research Institute of Pharmaceutical Sciences, Seoul National 
      University, Seoul, South Korea.
FAU - Kim, Hyeon-Ji
AU  - Kim HJ
AD  - College of Pharmacy, Seoul National University, Seoul, South Korea; Bio-MAX 
      Institute, Research Institute of Pharmaceutical Sciences, Seoul National 
      University, Seoul, South Korea.
FAU - Lee, In-Kyu
AU  - Lee IK
AD  - World Class University Program, Research Institute of Aging and Metabolism, 
      Kyungpook National University School of Medicine, Daegu, South Korea.
FAU - Lee, Mi-Ock
AU  - Lee MO
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140702
PL  - Netherlands
TA  - Int J Cardiol
JT  - International journal of cardiology
JID - 8200291
RN  - 0 (Nuclear Receptor Subfamily 1, Group F, Member 1)
RN  - 0 (RORA protein, human)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation/drug effects/*physiology
MH  - Enzyme Activation/physiology
MH  - Humans
MH  - Male
MH  - Muscle, Smooth, Vascular/drug effects/*enzymology
MH  - Myocytes, Smooth Muscle/drug effects/*enzymology
MH  - Nuclear Receptor Subfamily 1, Group F, Member 1/*administration & dosage
MH  - Rats
MH  - Rats, Sprague-Dawley
OTO - NOTNLM
OT  - AMPK
OT  - Atherosclerosis
OT  - RORalpha
OT  - vSMC proliferation
EDAT- 2014/07/16 06:00
MHDA- 2015/04/22 06:00
CRDT- 2014/07/15 06:00
PHST- 2014/01/29 00:00 [received]
PHST- 2014/05/05 00:00 [revised]
PHST- 2014/06/24 00:00 [accepted]
PHST- 2014/07/15 06:00 [entrez]
PHST- 2014/07/16 06:00 [pubmed]
PHST- 2015/04/22 06:00 [medline]
AID - S0167-5273(14)01110-3 [pii]
AID - 10.1016/j.ijcard.2014.06.043 [doi]
PST - ppublish
SO  - Int J Cardiol. 2014 Aug 20;175(3):515-21. doi: 10.1016/j.ijcard.2014.06.043. Epub 
      2014 Jul 2.