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

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.

Keywords: ACC; AMPK; Apoptosis; GAS6; Oxidative stress.