Proinflammatory stimuli engage brahma related gene 1 and brahma in endothelial injury

Fei Fang, Dewei Chen, Liming Yu, Xin Dai, Yuyu Yang, Wenfang Tian, Xian Cheng, Huihui Xu, Xinyu Weng, Mingming Fang, Jiliang Zhou, Yuqi Gao, Qi Chen, Yong Xu

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

RATIONALE: Endothelial dysfunction inflicted by inflammation is found in a host of cardiovascular pathologies. One hallmark event in this process is the aggregation and adhesion of leukocyte to the vessel wall mediated by the upregulation of adhesion molecules (CAM) in endothelial cells at the transcriptional level. The epigenetic modulator(s) of CAM transactivation and its underlying pathophysiological relevance remain poorly defined. OBJECTIVE: Our goal was to determine the involvement of Brahma related gene 1 (Brg1) and Brahma (Brm) in CAM transactivation and its relevance in the pathogenesis of atherosclerosis. METHODS AND RESULTS: In the present study, we report that proinflammatory stimuli augmented the expression of Brg1 and Brm in vitro in cultured endothelial cells and in vivo in arteries isolated from rodents. Overexpression of Brg1 and Brm promoted while knockdown of Brg1 and Brm abrogated transactivation of adhesion molecules and leukocyte adhesion induced by inflammatory signals. Brg1 and Brm interacted with and were recruited to the CAM promoters by nuclear factor κB/p65. Conversely, depletion of Brg1 and Brm disrupted the kinetics of p65 binding on CAM promoters and crippled CAM activation. Silencing of Brg1 and Brm also altered key epigenetic changes associated with CAM transactivation. Of intrigue, 17β-estradiol antagonized both the expression and activity of Brg1/Brm. Most importantly, endothelial-targeted elimination of Brg1/Brm conferred atheroprotective effects to Apoe mice on a Western diet. CONCLUSIONS: Our data suggest that Brg1 and Brm integrate various proinflammatory cues into CAM transactivation and endothelial malfunction and, as such, may serve as potential therapeutic targets in treating inflammation-related cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)986-996
Number of pages11
JournalCirculation research
Volume113
Issue number8
DOIs
StatePublished - Sep 27 2013

Keywords

  • Atherosclerosis
  • Brg1
  • Endothelial dysfunction
  • Epigenetics
  • Inflammation
  • Transcription

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Proinflammatory stimuli engage brahma related gene 1 and brahma in endothelial injury'. Together they form a unique fingerprint.

  • Cite this

    Fang, F., Chen, D., Yu, L., Dai, X., Yang, Y., Tian, W., Cheng, X., Xu, H., Weng, X., Fang, M., Zhou, J., Gao, Y., Chen, Q., & Xu, Y. (2013). Proinflammatory stimuli engage brahma related gene 1 and brahma in endothelial injury. Circulation research, 113(8), 986-996. https://doi.org/10.1161/CIRCRESAHA.113.301296