Myocardin-Related Transcription Factor A Mediates OxLDL-Induced Endothelial Injury

• Published in: Circulation research Vol. 108; no. 7; pp. 797 - 807
• Main Authors: Fang, Fei, Yang, Yuyu, Yuan, Zhibin, Gao, Yuqi, Zhou, Jiliang, Chen, Qi, Xu, Yong
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-04-2011; Lippincott Williams & Wilkins
• Subjects: Atherosclerosis - physiopathology; Biological and medical sciences; Cells, Cultured; DNA-Binding Proteins - physiology; Endothelium, Vascular - physiopathology; Epigenesis, Genetic - physiology; Fundamental and applied biological sciences. Psychology; Humans; Intercellular Adhesion Molecule-1 - physiology; Lipoproteins, LDL - physiology; NF-kappa B - physiology; Nitric Oxide Synthase Type III - physiology; Oncogene Proteins, Fusion - physiology; Serum Response Factor - physiology; Trans-Activators; Vertebrates: cardiovascular system; Vertebrata; Endothelial cell; Mammalia; Transcription; MRTF-A; oxLDL; ICAM-1; Circulatory system; Lesion; Transcription factor; Endothelium
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.240655

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.