Eleutheroside E decreases oxidative stress and NF-κB activation and reprograms the metabolic response against hypoxia-reoxygenation injury in H9c2 cells.

Ischemia-reperfusion (I/R) injury causes cardiac dysfunction through several mechanisms including oxidative stress and pro-inflammation. Eleutheroside E (EE) has protective effects in ischemia tissue and anti-inflammatory action. However, the effect of EE on I/R-injured cardiomyocytes is unknown. In this study, we used in vitro H9c2 cell model to investigate the favorable role of EE on myocardial I/R injury. We found that EE administration attenuated the cardiomyocyte apoptosis induced by hypoxia-reoxygenation (H/R) injury. Further, pre-treatment with EE dramatically inhibited mitochondrial oxidative stress, IκBα phosphorylation and nuclear factor kappa B (NF-κB) subunit p65 translocation into nuclei. EE might suppress the MAPK signaling pathway to inhibit the H/R-induced NF-κB activation. Moreover, we had analyzed the metabolomic profile of H/R-injured and H/R + 100 EE-treated H9c2 cells and found that the abundance of most metabolites changed by H/R could be re-modulated by EE treatment. Pathway analysis highlighted the inhibition of fatty acid biosynthesis and alternation of arginine and proline metabolism as two potential links to the favorable effect of EE on H/R-injured cardiomyocytes. The further demonstration showed that nitric oxide (NO), a product that is solely catabolized by l-arginine and has profound anti-oxidative stress activity during H/R in cardiomyocytes, was augmented by EE. Altogether, our results provide evidence that EE may be a potential drug for myocardial I/R injury by reducing oxidative stress, NF-κB activation, and metabolic reprogramming.