title: MicroRNA-638 is highly expressed in human vascular smooth muscle cells and inhibits PDGF-BB-induced cell proliferation and migration through targeting orphan nuclear receptor NOR1.
abstract: OBJECTIVE
  Aberrant vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to the development of vascular pathologies, such as atherosclerosis and restenosis. MicroRNAs have recently emerged as critical modulators in cellular processes and the purpose of this study is to identify novel miRNA regulators implicated in human aortic VSMC proliferation and migration.
  
  
  RESULTS
  To identify miRNAs that are differentially expressed in human VSMCs, we performed miRNA microarray analysis in human aortic smooth muscle cells (SMCs) at different time points after platelet-derived growth factor (PDGF) stimulation. Here, we identified microRNA-638 (miR-638) as a transcript that was one of the most significantly down-regulated in human VSMCs after PDGF stimulation. Furthermore, we confirmed, by Quantitative RT-PCR, that miR-638 is highly expressed in human VSMCs, and its expression is markedly down-regulated in a dose- and time-dependent manner upon PDGF treatment. Consistent with a critical role in SMC proliferation, we found that miR-638 expression was significantly up-regulated in human VSMCs cultured in differentiation medium, a condition that inhibits SMC proliferation. Furthermore, we identified the orphan nuclear receptor NOR1 as a downstream target gene product of miR-638 and down-regulation of NOR1 is critical for miR-638-mediated inhibitory effects on PDGF-induced cyclin D1 expression, cell proliferation, and migration in human aortic SMCs.
  
  
  CONCLUSIONS
  These results indicate that miR-638 is a key molecule in regulating human VSMC proliferation and migration by targeting the NOR1/cyclin D pathway and suggest that specific modulation of miR-638 in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.
authors.affiliation: Department of Cardiology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.forename: Guokun
authors.initials: G
authors.lastname: Wang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: You
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zhao
authors.forename: Ross
authors.initials: R
authors.lastname: Summer
authors.forename: Yongwen
authors.initials: Y
authors.lastname: Qin
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000077214:Becaplermin; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; C572154:MIRN638 microRNA, human; D035683:MicroRNAs; C490412:NR4A3 protein, human; D020574:Proto-Oncogene Proteins c-sis; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D019938:Cyclin D1; D000077214:Becaplermin
keywords: Migration; Orphan Nuclear Receptor NOR1; Proliferation; Vascular smooth muscle cell; miR-638
references.citation: J Cell Biol. 2010 Apr 5;189(1):13-22
references.pmid: 20351064
references.citation: Endocrinology. 2010 Sep;151(9):4356-67
references.pmid: 20610572
references.citation: J Biol Chem. 2009 Feb 6;284(6):3728-38
references.pmid: 19088079
references.citation: Cytokine Growth Factor Rev. 2004 Aug;15(4):237-54
references.pmid: 15207815
references.citation: Circ Res. 2010 Aug 20;107(4):501-11
references.pmid: 20558821
references.citation: Cardiovasc Res. 2013 Feb 1;97(2):302-10
references.pmid: 23042471
references.citation: Cancer Sci. 2011 Oct;102(10):1799-807
references.pmid: 21722265
references.citation: Nephrology (Carlton). 2012 May;17(4):346-51
references.pmid: 22295894
references.citation: Circulation. 2002 Sep 17;106(12):1530-5
references.pmid: 12234960
references.citation: J Biol Chem. 2006 Nov 3;281(44):33467-76
references.pmid: 16945922
references.citation: J Cell Physiol. 2011 Apr;226(4):1035-43
references.pmid: 20857419
references.citation: Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1762-9
references.pmid: 21378144
references.citation: EMBO Rep. 2011 Jan;12(1):56-62
references.pmid: 21109779
references.citation: Mol Med Rep. 2009 Nov-Dec;2(6):963-70
references.pmid: 21475928
references.citation: Circ Res. 2011 May 13;108(10):1180-9
references.pmid: 21474819
references.citation: Cardiovasc Res. 2012 Mar 15;93(4):594-604
references.pmid: 22065733
references.citation: J Clin Invest. 2005 Oct;115(10):2691-4
references.pmid: 16200204
references.citation: Circ Res. 2003 Jan 10;92(1):96-103
references.pmid: 12522126
references.citation: Trends Cardiovasc Med. 2006 Jan;16(1):25-8
references.pmid: 16387627
references.citation: J Biol Chem. 2010 Jan 29;285(5):3510-23
references.pmid: 19933579
references.citation: Genes Dev. 2009 Sep 15;23(18):2166-78
references.pmid: 19720868
references.citation: Circ Res. 2007 Jun 8;100(11):1579-88
references.pmid: 17478730
references.citation: Circ Res. 2000 Feb 4;86(2):125-30
references.pmid: 10666406
references.citation: Physiol Rev. 2004 Jul;84(3):767-801
references.pmid: 15269336
references.citation: Circ Res. 2009 Feb 27;104(4):476-87
references.pmid: 19150885
references.citation: Circ Res. 2009 Mar 27;104(6):742-9
references.pmid: 19213954
references.citation: Circ Res. 2009 Jul 17;105(2):158-66
references.pmid: 19542014
references.citation: J Biol Chem. 1982 Oct 10;257(19):11256-60
references.pmid: 7118883
references.citation: Arterioscler Thromb Vasc Biol. 2008 May;28(5):812-9
references.pmid: 18276911
references.citation: Toxicol Sci. 2012 Feb;125(2):382-91
references.pmid: 22048643
references.citation: Circ Cardiovasc Interv. 2011 Feb 1;4(1):104-11
references.pmid: 21325199
references.citation: Trends Cardiovasc Med. 2007 Apr;17(3):105-11
references.pmid: 17418373
references.citation: Neth Heart J. 2007;15(3):100-8
references.pmid: 17612668
references.citation: Virology. 2010 Mar 1;398(1):57-67
references.pmid: 20006370
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1118-26
references.pmid: 20378849
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):E423-31
references.pmid: 22308344
references.citation: EMBO J. 2010 Feb 3;29(3):559-73
references.pmid: 20019669
references.citation: Annu Rev Physiol. 2013;75:69-93
references.pmid: 23157557
references.citation: Curr Opin Hematol. 2012 May;19(3):224-31
references.pmid: 22406821
references.citation: J Thromb Haemost. 2007 Aug;5(8):1766-73
references.pmid: 17596136
references.citation: J Cell Physiol. 1986 Oct;129(1):11-9
references.pmid: 3760032
references.citation: Nature. 2009 Aug 6;460(7256):705-10
references.pmid: 19578358
references.citation: Crit Care Med. 2011 Apr;39(4):738-45
references.pmid: 21263323
references.citation: Genes Dev. 2008 May 15;22(10):1276-312
references.pmid: 18483217
references.citation: Arterioscler Thromb Vasc Biol. 2011 Sep;31(9):2044-53
references.pmid: 21817107