Myocardin-related transcription factor a mediates OxLDL-induced endothelial injury

Fei Fang, Yuyu Yang, Zhibin Yuan, Yuqi Gao, Jiliang Zhou, Qi Chen, Yong Xu

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Rationale: 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)797-807
Number of pages11
JournalCirculation research
Volume108
Issue number7
DOIs
StatePublished - Apr 1 2011

Keywords

  • ICAM-1
  • MRTF-A
  • endothelial cell
  • oxLDL
  • transcription

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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