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GAS6/Axl is associated with AMPK activation and attenuates H2O2-induced oxidative stress

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Abstract

Oxidative stress plays a key part in cardiovascular event. Growth arrest-specific gene 6 (GAS6) is a vitamin K-dependent ligand which has been shown to exert important effects in heart. The effects of GAS6 were evaluated against hydrogen peroxide (H2O2) ‑induced oxidative stress injury in HL-1 cardiomyocytes. A series of experimental methods were used to analyze the effects of GAS6 on cell viability, apoptosis, oxidative stress, mitochondrial function and AMPK/ACC signaling in H2O2‑injured HL-1 cells. In this study, we found that H2O2 reduced cell viability, increased apoptotic rate and intracellular reactive oxygen species (ROS). Meanwhile, H2O2 decreased the protein levels of GAS6, and increased the protein level of p-AMPK/AMPK, p-ACC/ACC. Then, we observed that overexpression of GAS6 significantly reduced cell death, manifested as increased cell viability, improved oxidative stress, apoptosis and upregulated the levels of GAS6, p-Axl/Axl, Nrf2, NQO1, HO-1, Bcl-2/Bax, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-ACC/ACC-related protein expression in HL-1 cells and H2O2‑injured cardiomyocytes. To further verify the results, we successfully constructed GAS6 lentiviral vectors, and found GAS6 shRNA partially reversed the above results. These data suggest that AMPK/ACC may be a downstream effector molecule in the antioxidant action of GAS6. In summary, our findings indicate that activation GAS6/Axl-AMPK signaling protects H2O2‑induced oxidative stress which is accompanied by the amelioration of oxidative stress, apoptosis, and mitochondrial function.

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Funding

This work was supported by Youth Science and Technology Rising Star Project of Shaanxi Province (2020KJXX-036), and Innovation Capability Strong Foundation Plan of Xi’an City (Medical Research Project, 21YXYJ0037).

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East, 450052, Zhengzhou, China

    Zhenxing Liang, Kehan Chen & Jing Xu

  2. Key Laboratory of Resource Biology and Biotechnology in Western China, Faculty of Life Sciences, Ministry of Education, Northwest University, 229 Taibai North Road, Xi’an, China

    Yang Yang, Xue Wu, Chenxi Lu, Aizhen Zhao & Xiyang Li

  3. Department of General Surgery, Tangdu Hospital, The Airforce Medical University, 1 Xinsi Road, 710038, Xi’an, China

    Huadong Zhao

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  1. Zhenxing Liang
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Liang, Z., Yang, Y., Wu, X. et al. GAS6/Axl is associated with AMPK activation and attenuates H2O2-induced oxidative stress. Apoptosis 28, 485–497 (2023). https://doi.org/10.1007/s10495-022-01801-5

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