Sirtuin3 attenuates pressure overload-induced pathological myocardial remodeling by inhibiting cardiomyocyte cuproptosis

Abstract

Pathological myocardial remodelling is the initiation of pressure overload-induced heart failure, and its involvement in the associated molecular mechanisms remains to be fully elucidated. The aim of this study was to investigate whether Sirtuin3 (SIRT3) can affect pathological myocardial remodeling by regulating cellular cuproptosis and its potential mechanisms. In this study, we found that pressure overload induced pathologic myocardial remodeling in which cardiomyocytes showed a distinct cuproptosis signature accompanied by downregulation of SIRT3 expression. In vitro experiments demonstrated that copper ions reduced SIRT3 expression by 40 % (p < 0.01) via lysosomal degradation. In vivo validation showed that pressure overload reduced SIRT3 expression by 35 % (p < 0.01) in myocardial tissue. And SIRT3 knockdown increased pressure overload-induced pathological myocardial remodeling and cardiomyocyte cuproptosis. In contrast, cardiomyocytes-specific overexpression of SIRT3 by adeno-associated virus vectors attenuated pressure overload-induced pathologic myocardial remodeling and was unaffected by circulating levels of copper ions and hepatic and renal impairment. Mechanistically, the reduction of SIRT3 induced cardiomyocytes to become copper ion-sensitive state cells by affecting the binding of copper ion transporter proteins to microtubule-associated protein 1 light chain 3 beta(LC3B) in cardiomyocytes. Disturbance of copper ion homeostasis in cardiomyocytes leads to accumulation of copper ions in cardiomyocytes and the development of cuproptosis. These findings elucidate a novel mechanism by which SIRT3 affects cardiomyocyte death in pressure overload-induced pathologic myocardial remodeling and suggest the great potential of SIRT3-regulated cuproptosis of cardiomyocytes in the prevention or treatment of pathologic myocardial remodeling.