title: Myocardin-related transcription factor A mediates OxLDL-induced endothelial injury.
abstract: BACKGROUND
  Atherosclerosis proceeds through a multistep reaction that begins with endothelial injury caused by a host of stress signals, among which oxidized low-density lipoprotein (oxLDL) plays a critical role. OxLDL disrupts normal functionality of the endothelium by upregulating adhesion molecules (eg, ICAM-1) and concomitantly downregulating endothelial nitric oxide synthase (eNOS) expression. The transcriptional modulator that mediates the cellular response to oxLDL remains largely obscure.
  
  
  OBJECTIVE
  Our goal was to determine whether myocardin-related transcription factor (MRTF)-A, a key protein involved in the transcriptional regulation of smooth muscle cell phenotype, is responsible for the endothelial injury by oxLDL, and, if so, how MRTF-A promotes the proatherogenic agenda initiated by oxLDL.
  
  
  RESULTS
  OxLDL stimulated the expression of MRTF-A in endothelial cells as evidenced by Western blotting and immunofluorescence. Overexpression of MRTF-A synergistically enhanced the induction of ICAM-1 and suppression of eNOS by oxLDL. In contrast, disruption of MRTF-A, either by small interfering RNA or dominant negative mutation, abrogated the pathogenic program triggered by oxLDL. Finally, chromatin immunoprecipitation assays indicate that oxLDL preferentially augmented MRTF-A binding to ICAM-1 and eNOS promoters and that MRTF-A drove differential epigenetic alterations taking place on these promoters in response to oxLDL.
  
  
  CONCLUSIONS
  Therefore, our data provide the first demonstration that MRTF-A is critically linked to pivotal pathophysiological events in the vascular endothelium.
authors.affiliation: Nanjing Medical University, 140 Hanzhong Rd., Nanjing, Jiangsu, China. yxu2005@gmail.com
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yuan
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Gao
authors.forename: Jiliang
authors.initials: J
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D050197:Atherosclerosis / Q000503:physiopathology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D044127:Epigenesis, Genetic / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D008077:Lipoproteins, LDL / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D026362:Serum Response Factor / Q000502:physiology; D015534:Trans-Activators
chemical_list: D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; C431575:MRTFA protein, human; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor; D015534:Trans-Activators; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III