Brg1 deficiency in vascular endothelial cells blocks neutrophil recruitment and ameliorates cardiac ischemia-reperfusion injury in mice

Increased neutrophil infiltration and the ensuing inflammatory response represent a hallmark event in cardiac ischemia-reperfusion injury (IRI). It remains poorly defined how the epigenetic machinery contributes to this process. Here we report that mice with endothelial specific deletion of brahma r...

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Bibliographic Details
Published in:International journal of cardiology 2018-10, Vol.269, p.250-258
Main Authors: Zhang, Xinjian, Liu, Shuai, Weng, Xinyu, Zeng, Sheng, Yu, Liming, Guo, Junli, Xu, Yong
Format: Article
Language:English
Subjects:
Animals
Cardiac ischemia-reperfusion injury
Cell Line, Transformed
DNA Helicases - deficiency
DNA Helicases - immunology
Endothelial cell
Endothelial Cells - immunology
Endothelial Cells - metabolism
Epigenetics
Humans
Inflammation
Mice
Mice, Knockout
Myocardial Reperfusion Injury - immunology
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - prevention & control
Neutrophil
Neutrophil Infiltration - physiology
Nuclear Proteins - deficiency
Nuclear Proteins - immunology
Transcription Factors - deficiency
Transcription Factors - immunology
Transcriptional regulation
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Summary:Increased neutrophil infiltration and the ensuing inflammatory response represent a hallmark event in cardiac ischemia-reperfusion injury (IRI). It remains poorly defined how the epigenetic machinery contributes to this process. Here we report that mice with endothelial specific deletion of brahma related gene 1 (BRG1), a chromatin remodeling protein, exhibited amelioration when subjected to cardiac ischemia-reperfusion as evidenced by a reduction in infarct size as well as better recovery of heart function. Endothelial BRG1 deficiency also attenuated cardiac fibrosis following IRI when compared to wild type littermates. Interestingly, ablation of BRG1 in the endothelium suppressed neutrophil infiltration and down-regulated the levels of pro-inflammatory mediators in the heart following IRI. Further studies revealed that BRG1 activated the transcription of PODOCALYXIN (PODXL), an L-SELECTIN ligand crucial for neutrophil adhesion, in vascular endothelial cells in response to hypoxia-reoxygenation (HR). BRG1 knockdown by small interfering RNA abrogated HR-induced PODXL expression and blocked the adhesion of neutrophils to endothelial cells. Mechanistically, BRG1 alters the chromatin structure surrounding the PODXL promoter by interacting with JMJD2B, a histone H3K9 demethylase. Depletion of JMJD2B abrogated PODXL induction by HR and inhibited the adhesion of neutrophils to endothelial cells. Our data suggest that trans-activation of PODXL by the BRG1-JMJD2B complex in endothelial cells may promote neutrophil infiltration and consequently the pathogenesis of cardiac ischemia-reperfusion injury. •Endothelial BRG1 deletion alleviates cardiac ischemia-reperfusion injury and fibrosis.•Endothelial BRG1 deletion ameliorates neutrophil infiltration and cardiac inflammation.•BRG1 activates podocalyxin transcription to regulate neutrophil adhesion.•BRG1 recruits histone demethylase JMJD2B to activate podocalyxin transcription.
ISSN:0167-5273
1874-1754
DOI:10.1016/j.ijcard.2018.07.105