Myocardin-related transcription factor A mediates OxLDL-induced endothelial injury.

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.

journal_name

Circ Res

journal_title

Circulation research

authors

Fang F,Yang Y,Yuan Z,Gao Y,Zhou J,Chen Q,Xu Y

doi

10.1161/CIRCRESAHA.111.240655

subject

Has Abstract

pub_date

2011-04-01 00:00:00

pages

797-807

issue

7

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.111.240655

journal_volume

108

pub_type

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