Sacubitril/valsartan attenuated myocardial inflammation, fibrosis, apoptosis and promoted autophagy in doxorubicin-induced cardiotoxicity mice via regulating the AMPKα-mTORC1 signaling pathway

Abstract

Background This study aimed to investigate the potential cardio-protective effects of sacubitril/valsartan (Sac/Val) in mice with doxorubicin (DOX)-induced cardiomyopathy, a common manifestation of cancer therapy-related cardiac dysfunction (CTRCD) associated with DOX. Methods A total of 24 mice were equally classified into 4 groups; control group, DOX (total 24 mg/kg), Sac/Val (80 mg/kg), and Sac/Val + DOX (Sac/Val was given from seven day before doxorubicin administration). Neonatal rat ventricular myocytes was exposed to 5 µM of DOX for 6 h in vitro to mimic the in vivo conditions. A variety of techniques were used to investigate cardiac inflammation, fibrosis, apoptosis, and autophagy, including western blot, real time quantitative PCR (RT-qPCR), immunohistochemistry, and fluorescence. Results Mice with Dox-induced cardiotoxicity displayed impaired systolic and diastolic function, characterized by elevated levels of cardiac inflammation, fibrosis, cardiomyocyte hypertrophy, apoptosis, and autophagy inhibition in the heart. Treatment with Sac/Val partially reversed these effects. In comparison to the control group, the protein expression of NLRP3, caspase-1, Collagen I, bax, cleaved caspase-3, and P62 were significantly increased, while the protein expression of bcl-2 and LC3-II were significantly decreased in the myocardial tissues of the Dox-induced cardiomyopathy group. The administration of Sac/Val demonstrated the potential to partially reverse alterations in protein expression within the myocardium of mice with Dox-induced cardiotoxicity by modulating the AMPKα-mTORC1 signaling pathway and suppressing oxidative stress. Additionally, Sac/Val treatment may mitigate Dox-induced apoptosis and inhibition of autophagy in primary cardiomyocytes. Conclusion Sac/Val seems to be cardio-protective against Dox-induced cardiotoxicity in pretreatment mice model. These findings could be attributed to the anti-inflammatory, antioxidant, anti-apoptotic and de-autophagy effects of Sac/Val through regulation of the AMPKα-mTORC1 signaling pathway.