Che-1 attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by upregulation of Nrf2 signaling.

Abstract

Hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis plays a critical role in the development of myocardial infarction. Che-1 has been reported as an anti-apoptotic gene in response to various cellular stresses. However, whether Che-1 regulates cardiomyocyte apoptosis in myocardial infarction remains unclear. In this study, we aimed to investigate the role of Che-1 in regulating H/R-induced cardiomyocyte apoptosis and the underlying molecular mechanism. The expression of mRNA and protein was detected by Real-time quantitative polymerase chain reaction and Western blot. Cell viability was detected by cell counting kit-8 assay. Cell cytotoxicity was measured by lactate dehydrogenase assay. Cell apoptosis was assessed by caspase-3 activity assay. Intracellular ROS generation was determined using a Reactive Oxygen Species Assay Kit. The activity of antioxidant response elements was detected by luciferase reporter assay. We found that Che-1 expression was significantly upregulated in cardiomyocytes in response to H/R treatment. Functional experiments showed that silencing of Che-1 promoted H/R-induced cell apoptosis and oxidative stress. By contrast, overexpression of Che-1 significantly alleviated H/R-induced cell apoptosis and oxidative stress. Interestingly, we found that Che-1 promoted the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the activity of antioxidant response elements. Moreover, Che-1 significantly upregulated the expression of Nrf2 downstream target genes, including heme oxygenase-1 and NADPH-quinone oxidoreductase 1. Our results showed that Che-1 alleviates H/R-induced cardiomyocyte apoptosis by upregulation of Nrf2 signaling. Our study suggests that Che-1 may serve as a potential and promising therapeutic target for the treatment of myocardial infarction.