Dual roles of chromatin remodeling protein BRG1 in angiotensin II-induced endothelial-mesenchymal transition

Endothelial-mesenchymal transition (EndMT) is considered one of the processes underlying tissue fibrosis by contributing to the pool of myofibroblasts. In the present study, we investigated the epigenetic mechanism whereby angiotensin II (Ang II) regulates EndMT to promote cardiac fibrosis focusing on the role of chromatin remodeling protein BRG1. BRG1 knockdown or inhibition attenuated Ang II-induced EndMT, as evidenced by down-regulation ofCDH5, an endothelial marker, and up-regulation ofCOL1A2, a mesenchymal marker, in cultured vascular endothelial cells. On the one hand, BRG1 interacted with and was recruited by Sp1 to theSNAI2(encoding SLUG) promoter to activateSNAI2transcription in response to Ang II stimulation. Once activated, SLUG bound to theCDH5promoter to repressCDH5transcription. On the other hand, BRG1 interacted with and was recruited by SRF to theCOL1A2promoter to activateCOL1A2transcription. Mechanistically, BRG1 evicted histones from the target promoters to facilitate the bindings of Sp1 and SRF. Finally, endothelial conditional BRG1 knockout mice (CKO) exhibited a reduction in cardiac fibrosis, compared to the wild type (WT) littermates, in response to chronic Ang II infusion. In conclusion, our data demonstrate that BRG1 is a key transcriptional coordinator programming Ang II-induced EndMT to contribute to cardiac fibrosis.