Ginsenoside Rh1 mitigates mitochondrial dysfunction induced by myocardial ischaemia through its novel role as a sirtuin 3 activator

BACKGROUND AND PURPOSE: The sirtuin 3 (SIRT3) signalling pathway is an essential target for various cardiovascular diseases (CVDs), although effective interventions in myocardial ischaemia-induced mitochondrial dysfunction remain to be elucidated. Here, we discovered a potent SIRT3 activator and explored its efficacy and mechanism against mitochondrial dysfunction. EXPERIMENTAL APPROACH: Molecular docking screened for SIRT3 activators among the 10 more common rare ginsenosides. In vivo, left coronary artery ligation induced myocardial ischaemia injury, followed by echocardiography, histopathology and serum biochemical indicators, in C57BL/6J mice. Expression levels of mitophagy and mitochondrial dynamics-associated proteins were examined by western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC). In vitro, oxygen-glucose deprivation-induced hypoxic injury in neonatal rat ventricular myocytes, and cell viability and mitochondrial function were investigated. SIRT3 small interference RNA (siRNA) was transfected into cardiomyocytes to validate mitochondrial dynamics and mitophagy mechanism regulated by ginsenoside Rh1. KEY RESULTS: Rh1 exhibited the strongest binding affinity as an effective activator of SIRT3. Rh1 improved cardiac function and mitigated myocardial ischaemia injury in vivo. Rh1 ameliorated oxidative stress, improved mitochondrial network morphology and mitochondrial respiration function in hypoxia-injured cardiomyocytes. Rh1 bound to SIRT3 and simultaneously up-regulated Foxo3a, facilitating its nuclear translocation and reducing acetylation of Foxo3a. Rh1 markedly promoted mitochondrial fusion, inhibited mitochondrial fission and accelerated mitophagy. SIRT3 siRNA abrogated the regulation of Rh1 on oxidative stress, mitochondrial dynamics and mitophagy. CONCLUSION AND IMPLICATIONS: Rh1 is a novel SIRT3 activator and protects against myocardial ischaemia-induced mitochondrial dysfunction, providing new clues to prevent and treat ischaemic injury-associated CVD.