Atorvastatin treatment ameliorates cardiac function and remodeling induced by isoproterenol attack through mitigation of ferroptosis

Abstract

Ferroptosis has been identified as an important role in damaged heart. Meanwhile, statin therapy has been reported to be beneficial for the treatment of heart failure(HF) under different conditions. However, the beneficial effects of statin treatment on regulation of ferroptosis in failing heart is unveiled. The aim of this study is to explore the protective efficacy of atorvastatin against the ferroptosis related signaling pathway in isoproterenol(ISO)-induced HF. We found that ATV and ferrostatin-1(Fer-1,as a positive control) significantly improved ISO-decreased cell viability and cell survival by reducing oxidative stress and Fe2+-dependent lipid peroxidation in H9C2 cells. Additionally, ISO triggered marked ferritinophagy accompanied by up-regulating protein levels of LC3BII,NCOA4 and Beclin1 and down-regulating protein levels of P62 and FTH1 in damaged cells, which nevertheless was significantly blocked by administration of ATV and these results were in parallel with the results obtained after 3-methyadenine(3-MA) treatment. Consistently, C57BL/6J mice were used in used in this study and administered 5 mg/kg/day ISO for 2 weeks to simulate cardiac injury. 20 mg/kg/day ATV treatment for 2 weeks simultaneously markedly improved cardiac dysfunction and remodeling induced by ISO attack. ATV showed significantly protective effects through suppressing the activation of ferroptosis related signaling, as evidenced by decreasing the mRNA levels of PTGS2(a marker of ferroptosis), contents of malonaldehyde and protein levels of NOX4 and increasing the contents of glutathione(GSH), the ratio of GSH/GSSG and protein levels of GPX4 and SLC7A11. Moreover, ISO evidently triggered degradation of FTH1 in failing heart. However, ATV significantly prevented these changes in damaged heart. Overall, these results reveal atorvastatin suppresses ferroptosis and exhibits protective effect on failing myocardium of mice after ISO insult though inhibiting ferritinophagy-mediated ferroptosis, which might be a potential therapeutic strategy in the prevention of ISO-associated cardiomyopathy.