Abnormalities in the SIRT1-SIRT3 axis promote myocardial ischemia-reperfusion injury through ferroptosis caused by silencing the PINK1/Parkin signalling pathway

Abstract

Abstract Myocardial ischemia-reperfusion injury (MIRI) is the main reason for the poor prognosis of patients with ischemic cardiomyopathy (ICM). To date, the mechanism of MIRI remains unknown. As members of the silent information regulator 2 (SIR2) family, SIRT1 and SIRT3 have been shown to play critical roles in protecting cardiomyocytes against MIRI, but whether SIRT1 and SIRT3 interact to regulate mitophagy and their association with ferroptosis during MIRI have not been reported. Hence, in this study, we investigated the role and specific mechanism of SIRT1 and SIRT3 in protecting cardiomyocytes against MIRI through bioinformatics analysis and cell experiment methods. Meanwhile, we also elucidated the interaction between SIRT1 and SIRT3 during MIRI. We found that the expression of SIRT1 and SIRT3 in myocardial tissues and the peripheral blood of patients with ICM was abnormal, and SIRT1 was significantly negatively correlated with SIRT3 during MIRI. Further analysis revealed that the SIRT1-SIRT3 axis was closely correlated with ferroptosis, and its silencing could effectively increase the incidence of ferroptosis. Furthermore, SIRT1-SIRT3 axis silencing was accompanied by changes in PINK1, Parkin, P62/SQSTM1 and LC3 expression. PINK1 silencing significantly increased the incidence of ferroptosis, while resveratrol (Res) and/or honokiol (HKL) effectively reversed the outcome. These results suggests that abnormalities in the SIRT1-SIRT3 axis promote MIRI through ferroptosis caused by silencing the PINK1/Parkin signalling pathway, which may provide promising therapeutic prospects for patients with ICM.