Abstract 578: Brg1 Protects Cardiomyocytes Against Oxidative Damage Through Activation of the Nrf2 Signaling Pathway in Acute Myocardial Infarction

Background: Brahma-related gene 1 (Brg1), the core ATPase subunit of a large chromatin remodeling complex, plays critical role in the regulation of gene expression during cardiac growth, differentiation. In adults, Brg1 is turned off in cardiomyocytes and reactivated by cardiac stress. How Brg1 in myocardial infarction (MI) is poorly understood. The Keap1-Nrf2-ARE pathway plays an important role in the development of MI. However, by which Nrf2 activation is mediated in MI still remains to be determined.

Methods and results: In vivo, adult male C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery for MI model. Our data demonstrated that in peri-infarct zone, the protein of Brg1 was significantly increased 7 days after MI compared with the sham group, accompanied by Nrf2 nuclear translocation, and upregulation of the expressions of NQO1, GSTP1, HO1. We further revealed that with adenoviral intramyocardial injection, the Brg1 overexpression reduced the percentage myocardial infarct, improved cardiac dysfunction, decreased the relative fluorescence intensity of ROS with fluorescent probe DHE in MI mice. Conversely, shRNA-mediated knockdown of Brg1 enlarged the percentage myocardial infarct, exacerbated cardiac dysfunction, increased the relative fluorescence intensity of ROS. More importantly, the Brg1 overexpression significantly induced Nrf2 translocation from cytoplasm to nuclear and upregulated NQO1, GSTP1 and HO1 expressions. Whereas Brg1 knockdown decreased the level of Nrf2 protein in the nucleus, suppressed NQO1,GSTP1 and HO1 expressions. In vitro, Oxygen-Glucose deprivation(OGD) on neonatal cardiomyocytes was established. The effects of Brg1 on OGD and Nrf2 activation were observed with gain- and loss-of-function approaches to regulate Brg1 expression. The results were consistent with in vivo study. Moreover, the down-regulation of Nrf2 by brusatol inhibited the increase of these antioxidative genes induced by Brg1 overexpression.

Conclusions: This study indicated that Brg1-induced cardiac protection was partially mediated through transcription activator Nrf2. The Brg1-Nrf2-ARE pathway may represent a novel therapeutic target for preventing cardiac dysfunction in patients with MI.