BACKGROUND: Cardiac remodeling Post-Myocardial Infarction (MI) drives heart failure. Geniposide (GP), a traditional Chinese medicine-derived compound, exhibits cardioprotective potential, yet its mechanisms remain unclear. This study explored the GP's role in post-MI remodeling via Parkin-dependent mitophagy.
METHODS: Murine MI and cardiomyocyte Chronic Hypoxia (CH) models were established. MI mice received GP; cardiac function, histopathology, apoptosis, fibrosis/autophagy markers, and mitochondrial clearance were assessed. in vitro, Parkin-silenced hypoxic cardiomyocytes were used to evaluate GP's effects on viability, oxidative stress, mitochondrial function, autophagy proteins, and autophagosome formation.
RESULTS: in vivo, GP improved cardiac function, reduced fibrosis/apoptosis, and suppressed fibrosis-related genes (Col1a1, Col3a1, Tgfb1, Mmp9). GP enhanced clearance of damaged mitochondria via autophagy, mitigating oxidative stress. in vitro, GP's protection against hypoxia required Parkin: it preserved mitochondrial homeostasis, inhibited ROS-mediated apoptosis, and reduced autophagosome accumulation. Mechanistically, GP attenuated excessive mitophagy by modulating Parkin, thereby maintaining mitochondrial quality and reducing oxidative injury.
CONCLUSION: GP alleviates post-MI remodeling by suppressing Parkin-dependent hyperactivated mitophagy, reducing cardiomyocyte loss and fibrosis. Parkin is central to GP's therapeutic effects, highlighting its potential as a target for MI-related heart failure. This study elucidates GP's cardioprotective mechanism and proposes Parkin pathway modulation as a novel strategy to counteract pathological cardiac remodeling.
