Background: 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. Methods and results: 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. Conclusion: 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.
Bibliographical noteFunding Information:
This work was supported, in part, by grants from the National Natural Science Foundation of China (81725001, 81460042, 81770487) and Haihan Province R&D Fund Key Project (ZDYF2018102).
This work was supported, in part, by grants from the National Natural Science Foundation of China ( 81725001 , 81460042 , 81770487 ) and Haihan Province R&D Fund Key Project ( ZDYF2018102 ).
- Cardiac ischemia-reperfusion injury
- Endothelial cell
- Transcriptional regulation
PubMed: MeSH publication types
- Journal Article