Nceh1 protects against myocardial ischemia/reperfusion injury by suppressing oxidative stress and apoptosis

Our previous research found that expression of Nceh1 in cardiac tissue decreased obviously in the myocardial ischemia/reperfusion (MI/R) injury model, but the relationship between Nceh1 and MI/R damage has not been observed. In this study, 933 coronary artery disease (CAD) patients were enrolled, DNA methylation status was detected with an Illumina 850 K chip, and the patients were followed up. We upregulated expression of Nceh1 in MI/R-induced cardiomyocyte injury models in vivo and in vitro to observe whether Nceh1 regulated myocardial injury. The results demonstrated that DNA methylation of cg14338526 was significantly positively associated with the risk of death CAD patients, moreover, pearson correlation analysis revealed that DNA methylation level of cg14338526 was negatively associated with the mRNA level of Nceh1 , suggesting that expression of Nceh1 transcriptional levels inversely predicted CAD mortality risk. By applying rat MI/R model and cardiomyocyte injury model of H9C2 cells, the experimental evidence demonstrated that Nceh1 overexpression markedly attenuated MI/R injury through suppression of oxidative stress (OS) and apoptotic pathways. In order to investigate the mechanism of how Nceh1 inhibits OS and apoptosis, according to the result of RNA sequencing, our results showed that the Nrf2/HO-1 signaling activity significantly enhanced, overexpression of Nceh1 activated the Nrf2/HO-1 pathway. H9C2 cells were pretreated with Nrf2/HO-1 pathway inhibitor ML-385, the results demonstrated that ML−385 abolished the protective effects of Nceh1 overexpression, as evidenced by decreased cell survival and increased OS and apoptosis. In conclusion, Nceh1 suppresses OS and apoptosis via Nrf2/HO−1 activation, thereby attenuating MI/R injury.