title: MicroRNA-663 regulates human vascular smooth muscle cell phenotypic switch and vascular neointimal formation.
abstract: BACKGROUND
  Abnormal phenotypic switch of vascular smooth muscle cell (VSMC) is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. MicroRNAs (miRNAs) have emerged as important regulators for VSMC function, and we recently identified miR-663 as critical for controlling human aortic smooth muscle cell proliferation.
  
  
  OBJECTIVE
  To investigate whether miR-663 plays a role in human VSMC phenotypic switch and the development of neointima formation.
  
  
  RESULTS
  By using quantitative reverse-transcription polymerase chain reaction, we found that miR-663 was significantly downregulated in human aortic VSMCs on platelet-derived growth factor treatment, whereas expression was markedly increased during VSMC differentiation. Furthermore, we demonstrated that overexpression of miR-663 increased expression of VSMC differentiation marker genes, such as smooth muscle 22α, smooth muscle α-actin, calponin, and smooth muscle myosin heavy chain, and potently inhibited platelet-derived growth factor-induced VSMC proliferation and migration. We identified the transcription factor JunB and myosin light chain 9 as downstream targets of miR-663 in human VSMCs, because overexpression of miR-663 markedly inhibited expression of JunB and its downstream molecules, such as myosin light chain 9 and matrix metalloproteinase 9. Finally, we showed that adeno-miR-663 markedly suppressed the neointimal lesion formation by ≈50% in mice after vascular injury induced by carotid artery ligation, specifically via decreased JunB expression.
  
  
  CONCLUSIONS
  These results indicate that miR-663 is a novel modulator of human VSMC phenotypic switch by targeting JunB/myosin light chain 9 expression. These findings suggest that targeting miR-663 or its specific downstream targets in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.
authors.affiliation: From the Center for Translational Medicine and Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA; and Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.forename: Ni
authors.initials: N
authors.lastname: Zhu
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.forename: Nadan
authors.initials: N
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Xiaohua
authors.initials: X
authors.lastname: You
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zhao
authors.forename: Charalambos C
authors.initials: CC
authors.lastname: Solomides
authors.forename: Yongwen
authors.initials: Y
authors.lastname: Qin
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D008840:Microfilament Proteins / Q000378:metabolism; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D058426:Neointima / Q000503:physiopathology*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000096985:Calponins
chemical_list: D000199:Actins; D002135:Calcium-Binding Proteins; D035683:MicroRNAs; D008840:Microfilament Proteins; D018995:Myosin Heavy Chains; D018994:Myosin Light Chains; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; D000096985:Calponins; C581727:JunB protein, human; C552243:MIRN663 microRNA, human
keywords: miR-663; migration; proliferation; vascular remodeling; vascular smooth muscle cells