Dihydromyricetin protects against Doxorubicin-induced cardiotoxicity through activation of AMPK/mTOR pathway

Background: Doxorubicin (DOX) is a highly effective broad-spectrum antitumor agent, but its clinical administration is limited by self-induced cardiotoxicity. Dihydromyricetin (DHM) is a flavonoid compound extracted from the Japanese raisin tree. Evidence that DHM has neovascular protective properties makes it a candidate for studying cardiotoxicity prevention strategy. However, it remains unknown if DHM can protect against cardiotoxicity caused by DOX. Purpose: The present study was performed to evaluate the protective effect of DHM on DOX-induced cardiotoxicity in vivo and in vitro. Methods: C57BL/6 mice were intraperitoneally injected with DOX to construct cardiac injury model in vivo, and AC16 cells were exposed to DOX to induce cell injury in vitro. Left ventricular function of mice were detected by echocardiography, the apoptosis of mice cardiac tissue and AC16 cells were detected by TUNEL and Hoechst33342/PI double staining. The expression of apoptosis and autophagy related proteins were detected by western blotting, immunohistochemical staining and immunofluorescence staining. Results: Echocardiographic results showed that DOX-induced cardiotoxicity were significantly alleviated by DHM pretreatment. DOX induced cardiotoxicity of mice by inhibiting AMPK activation, increasing apoptosis and decreasing autophagy. However, under the same conditions, the heart tissue of DHM-pretreated mice showed increased autophagy and decreased apoptosis via activation AMPK/mTOR pathway. The same results were observed in vitro, and it was also found that DHM can inhibit the production of intracellular ROS in vitro. Conclusion: DHM protects against cardiotoxicity by inhibiting apoptosis and oxidative stress and it can allevate theautophagy inhibition caused by DOX through AMPK/mTOR pathway. DHM preconditioning may be a breakthrough in protecting DOX-induced cardiotoxicity in the future clinical applications.