Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury

Abstract

Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to determine the role of Brahma-related gene 1 (Brg1), a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2/HO-1 pathway activation during hepatic ischemia-reperfusion (HIR). Our results showed that hepatic Brg1 was inhibited during early HIR while Brg1 overexpression reduced oxidative injury in CMV-Brg1 mice subjected to HIR. Moreover, promoter-driven luciferase assay showed that overexpression of Brg1 by adenovirus transfection in AML12 cells selectively enhanced HO-1 gene expression after hypoxia/reoxygenation (H/R) treatment but did not affect the other Nrf2 target gene NQO1. Furthermore, inhibition of HO-1 by the selective HO-1 inhibitor zinc protoporphyria could partly reverse the hepatic protective effects of Brg1 overexpression while HO-1-Adv attenuated AML12 cells H/R damage. Further, chromatin immunoprecipitation analysis revealed that Brg1 overexpression, which could significantly increase the recruitment of Brg1 protein to HO-1 but not NQO1 promoter, was recruited by Nrf2 to the HO-1 regulatory regions in AML12 hepatocytes subjected to H/R. In conclusion, our results demonstrated that restoration of Brg1 during reperfusion could enhance Nrf2-mediated inducible expression of HO-1 during HIR to effectively increase antioxidant ability to combat against hepatocytes damage.