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

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Abstract

Background

Metformin, a first-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 ethanol-induced 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 improved cell viability in cardiomyocytes exposed to ethanol. Furthermore, metformin suppressed cardiomyocyte apoptosis and reduced the expressions of apoptosis-related proteins (Bax and C-CAS-3). 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 protein expression was significantly inhibited in ethanol-treated cardiomyocytes, 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.

Conclusion

In summary, our study provides the first 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.

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Data availability

All data that supports the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge and appreciate our colleagues for their valuable suggestions and technical assistance for this study.

Funding

This work was supported by the Natural Science Fund of Ningbo (202003N4251, 2022J223) and Science and Technology Innovation 2025 Major Project of Ningbo (2021Z018).

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Author notes

  1. Yunjie Chen and Suyan Zhu are co-first authors.

Authors and Affiliations

  1. Department of Pharmacy, Ningbo first Hospital, 315010, Ningbo, People’s Republic of China

    Yunjie Chen, Suyan Zhu, Zhu Lin, Yuanbin Zhang & Xuan Zhou

  2. Department of Traditional Chinese Medicine, Ningbo First Hospital, 315010, Ningbo, People’s Republic of China

    Xueqin Chen

  3. Central Laboratory of the Medical Research Center, Ningbo First Hospital, 315010, Ningbo, People’s Republic of China

    Yunjie Chen & Yuanbin Zhang

  4. School of Pharmaceutical Science, Wenzhou Medical University, 325000, Wenzhou, People’s Republic of China

    Cheng Jin & Shengqu He

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  1. Yunjie Chen
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Contributions

YC, SZ, ZL, XC and XZ conceived, designed and supervised the study. YC, YZ, CJ and SH performed the experiment and the data analyses. YC, XZ, CJ and ZL contributed to manuscript preparation and reversion. XC and SZ helped perform the analysis with constructive discussions. All authors read and approved the final manuscript.

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Correspondence to Xueqin Chen or Xuan Zhou.

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Chen, Y., Zhu, S., Lin, Z. et al. Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner. Mol Biol Rep 50, 3469–3478 (2023). https://doi.org/10.1007/s11033-023-08310-x

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