title: Myocardin regulates vascular smooth muscle cell inflammatory activation and disease.
abstract: OBJECTIVE
  Atherosclerosis, the cause of 50% of deaths in westernized societies, is widely regarded as a chronic vascular inflammatory disease. Vascular smooth muscle cell (VSMC) inflammatory activation in response to local proinflammatory stimuli contributes to disease progression and is a pervasive feature in developing atherosclerotic plaques. Therefore, it is of considerable therapeutic importance to identify mechanisms that regulate the VSMC inflammatory response.
  
  
  RESULTS
  We report that myocardin, a powerful myogenic transcriptional coactivator, negatively regulates VSMC inflammatory activation and vascular disease. Myocardin levels are reduced during atherosclerosis, in association with phenotypic switching of smooth muscle cells. Myocardin deficiency accelerates atherogenesis in hypercholesterolemic apolipoprotein E(-/-) mice. Conversely, increased myocardin expression potently abrogates the induction of an array of inflammatory cytokines, chemokines, and adhesion molecules in VSMCs. Expression of myocardin in VSMCs reduces lipid uptake, macrophage interaction, chemotaxis, and macrophage-endothelial tethering in vitro, and attenuates monocyte accumulation within developing lesions in vivo. These results demonstrate that endogenous levels of myocardin are a critical regulator of vessel inflammation.
  
  
  CONCLUSIONS
  We propose myocardin as a guardian of the contractile, noninflammatory VSMC phenotype, with loss of myocardin representing a critical permissive step in the process of phenotypic transition and inflammatory activation, at the onset of vascular disease.
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Ackers-Johnson
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Amarnath
authors.initials: A
authors.lastname: Talasila
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Sage
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Long
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.).
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Miano
authors.affiliation: From the Department of Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (M.A.-J., A.T., A.P.S., N.W.M., M.R.B., S.S.); Department of Medicine, AAB Cardiovascular Research Institute, West Henrietta, NY (X.L., J.M.M.); and Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (I.B.). ss661@cam.ac.uk.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sinha
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005838:Genotype; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D017208:Rats, Wistar; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099251:Myocardin
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin
keywords: atherosclerosis; inflammation; myocardin; smooth muscle