Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner

Abstract

Background Metformin, a rst-line oral anti-diabetic drug, has recently been reported to exert protective effect on various cardiovascular diseases. However, the potential role of metformin in ethanol-induced cardiomyocyte injury is still unknown. Therefore, this study was aimed to investigate the effect of metformin on ethanol-induced cardiomyocyte injury and its underlying mechanism.Methods and Results H9c2 cardiomyocytes were exposed to ethanol for 24 h to establish an ethanolinduced cardiomyocyte injury model, and followed by treatment with metformin in the presence or absence of Lapatinib (an ErbB2 inhibition). CCK8 and LDH assays demonstrated that metformin suppressed cardiomyocyte apoptosis induced by ethanol exposure. Furthermore, the up-regulated expressions of apoptosis-related proteins (Bax and C-CAS-3) were also reduced by metformin. In addition, our results showed that metformin activated the AKT/Nrf2 pathway, and then promoted Nrf2 nuclear translocation and the transcription of its downstream antioxidant genes (HO-1, CAT and SOD2), thereby inhibiting oxidative stress. Interestingly, we found that ErbB2 expression was signi cantly inhibited in ethanol-treated cardiomyocyte, which was markedly reversed by metformin. In contrast, Lapatinib largely abrogated the activation of AKT/Nrf2 signaling by metformin, accompanied by the increases in oxidative stress and cardiomyocyte apoptosis,indicating that metformin prevented ethanol-induced cardiomyocyte injury in an ErbB2-dependent manner.Conclusions In summary, our study provides the rst evidence that metformin protects cardiomyocyte against ethanol-induced oxidative stress and apoptosis by activating ErbB2-mediated AKT/Nrf2 signaling. Thus, metformin may be a potential novel treatment approach for alcoholic cardiomyopathy.

Ginsenoside Rg1 regulates autophagy and endoplasmic reticulum stress via the AMPK/mTOR and PERK/ATF4/CHOP pathways to alleviate alcohol‑induced myocardial injury

“…The present study using ethanol-stimulated H9c2 cells to investigate the roles of G-Rg1 in alcohol-induced myocardial injury; the same model has been used in previous studies (32)(33)(34). There is accumulating evidence to suggest that G-Rg1 protects against alcohol-induced liver injury (13)(14)(15).…”