BRG1 protects the heart from acute myocardial infarction by reducing oxidative damage through the activation of the NRF2/HO1 signaling pathway

Abstract

Brahma-related gene 1 (BRG1) regulates the chromatin structure and expression of cardiac genes. Although BRG1 is downregulated in adult cardiomyocytes, it is reactivated during cardiac stress. The role of BRG1 in acute myocardial infarction (AMI) has not been clearly defined. This study assessed the protective role of BRG1 in AMI using cell cultures and an animal model and explored the underlying molecular events. The results showed that in the peri-infarct zone, expression of BRG1 protein was significantly increased relative to the sham group, which was accompanied by NRF2 and HO1 upregulation and KEAP1 downregulation. BRG1 overexpression through adenoviral intramyocardial injection into AMI mice reduced the infarct size and improved cardiac functions with upregulation of NRF2 and its target HO1 and attenuated oxidative damage and cell apoptosis. However, shRNA-mediated Brg1 knockdown had the opposite effects. These results were further confirmed in cultured primary neonatal rat cardiomyocytes (NRCMs) with oxygen-glucose deprivation (OGD). Moreover, the selective NRF2 inhibitor brusatol could partially reverse cardiomyocyte antioxidant ability and BRG1 overexpression-induced cardiac protection in vitro. In addition, co-immunoprecipitation and immunofluorescence data showed that BRG1 overexpression significantly promoted the BRG1/NRF2 co-localization in cardiomyocytes. The chromatin immunoprecipitation-qPCR revealed BRG1 interaction with the Ho1 promoter and BRG1 overexpression could induce BRG1 binding to the Ho1 promoter during the OGD. In conclusion, this study demonstrated that BRG1 upregulation during AMI in vitro and in vivo increased the NRF2 level and NRF2 nuclear accumulation for HO1 expression to alleviate cardiac myocyte oxidative stress and upregulate cardiomyocyte viability. The BRG1-NRF2-HO1 pathway may represent a novel therapeutic target in the prevention of cardiac dysfunction in AMI patients.

Keywords: Brahma-related gene 1; Heme oxygenase-1; Myocardial infarction; Nuclear factor erythroid 2-related factor 2; Oxidative damage.