Simvastatin protects cardiomyocytes from doxorubicin cardiotoxicity by suppressing endoplasmic reticulum stress and activating Akt signaling

Doxorubicin is a widely used anti-cancer chemotherapy drug with high cardiotoxicity. Previous studies have reported the pleiotropic beneficial effects of simvastatin on cardiovascular system, it is still unknown whether it protects cardiomyocytes against doxorubicin cardiotoxicity. The present study aimed to investigate the role of simvastatin in doxorubicin induced cardiomyocyte apoptosis and the possible mechanisms. We found that simvastatin reduced serum cardiac enzymes such as LDH and CK and reversed the reduction of heart function induced by doxorubicin in mouse models. Mechanistically, we showed that simvastatin was able to inhibit ROS generation and apoptosis upon doxorubicin treatment, which is accompanied by reduction of proteins in endoplasmic reticulum (ER) stress, suggesting that suppression of ER stress associated death (ERAD) may confer the protective effect of simvastatin. Furthermore, we noted that the pro-survival Akt signaling was also activated by simvastatin. In summary, our work revealed for the first time that simvastatin alleviates doxorubicin cardiotoxicity by attenuating ER stress and activating Akt pathway, and simvastatin administration could be useful in the prevention of cardiotoxicity in cancer patients receiving doxorubicin treatment.