BRG1 regulates NOX gene transcription in endothelial cells and contributes to cardiac ischemia-reperfusion injury

Zilong Li, Xinjian Zhang, Shuai Liu, Sheng Zeng, Liming Yu, Guang Yang, Junli Guo, Yong Xu

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Excessive accumulation of reactive oxygen species (ROS) is considered a major culprit for a host of cardiovascular diseases. In vascular endothelial cells, ROS production is mediated by NAPDH oxidases (NOX). In the present study we investigated the role of the chromatin remodeling protein BRG1 in NOX trans-activation as well as its implication in cardiac ischemia-reperfusion injury. We report that in response to hypoxia-reoxygenation (HR) BRG1 was recruited to the NOX promoter regions in both immortalized endothelial cells and primary microvascular endothelial cells. BRG1 knockdown attenuated the induction of NOX genes by HR stimulation. Suppression of NOX trans-activation by BRG1 silencing was paralleled by the loss of active histone modifications (acetylation of histones H3 and H4) and the re-appearance of repressive histone modification (dimethylation of histone H3K9) surrounding the NOX promoter. Of interest, the H3K9 demethylase KDM3A bound to the NOX promoters with kinetics similar to BRG1 and interacted with BRG1 to activate NOX transcription. KDM3A depletion ameliorated NOX induction and ROS production in endothelial cells exposed to HR. Finally, mice with endothelial-specific deletion of BRG1 were protected from cardiac ischemia-reperfusion injury. In conclusion, our data suggest that BRG1 may link epigenetic activation of NOX transcription in endothelial cells to cardiac ischemia reperfusion injury.

Original languageEnglish (US)
Pages (from-to)3477-3486
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number10
DOIs
StatePublished - Oct 2018
Externally publishedYes

Keywords

  • Endothelial cell
  • Epigenetics
  • NOX
  • ROS
  • Transcriptional regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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