title: Myocardin regulates vascular response to injury through miR-24/-29a and platelet-derived growth factor receptor-β.
abstract: OBJECTIVE
  Myocardin, a potent transcriptional coactivator of serum response factor, is involved in vascular development and promotes a contractile smooth muscle phenotype. Myocardin levels are reduced during vascular injury, in association with phenotypic switching of smooth muscle cells (SMCs). However, the direct role of myocardin in vascular disease is unclear.
  
  
  RESULTS
  We show that re-expression of myocardin prevents the vascular injury response in murine carotid arteries, with reduced neointima formation due to decreased SMC migration and proliferation. Myocardin reduced SMC migration by downregulating platelet-derived growth factor receptor-β (PDGFRB) expression. Pdgfrb was regulated by myocardin-induced miR-24 and miR-29a expression, and antagonizing these microRNAs restored SMC migration. Furthermore, using miR-24 and miR-29a mimics, we demonstrated that miR-29a directly regulates Pdgfrb expression at the 3' untranslated region while miR-24 has an indirect effect on Pdgfrb levels. Myocardin heterozygous-null mice showed an augmented neointima formation with increased SMC migration and proliferation, demonstrating that endogenous levels of myocardin are a critical regulator of vessel injury responses.
  
  
  CONCLUSIONS
  Our results extend the function of myocardin from a developmental role to a pivotal regulator of SMC phenotype in response to injury, and this transcriptional coactivator may be an attractive target for novel therapeutic strategies in vascular disease.
authors.affiliation: From the Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (A.T., H.Y., M.A.-J., M.R.B., S.S.); and Division of Biopharmaceutics, Leiden/Amsterdam Centre for Drug Research, Leiden University, Einsteinweg, Leiden, The Netherlands (M.R.B., T.v.B., I.B.).
authors.forename: Amarnath
authors.initials: A
authors.lastname: Talasila
authors.forename: Haixiang
authors.initials: H
authors.lastname: Yu
authors.forename: Matthew
authors.initials: M
authors.lastname: Ackers-Johnson
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.forename: Theo
authors.initials: T
authors.lastname: van Berkel
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sinha
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099251:Myocardin
chemical_list: D020413:3' Untranslated Regions; D001057:Apolipoproteins E; D035683:MicroRNAs; D009687:Nuclear Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D015534:Trans-Activators; D000099251:Myocardin; C574736:MIRN24 microRNA, rat; C547014:MIRN29 microRNA, mouse; C526366:MIRN29 microRNA, rat; C529080:Mirn24 microRNA, mouse
keywords: carotid arteries; microRNAs; muscle, smooth; myocardin; signal transduction