Betulinic acid attenuates lipopolysaccharide-induced cardiac injury by promoting mitophagy with enhancing PINK1/Parkin and suppressing BNIP3

Abstract

Betulinic acid (BA), a natural pentacyclic triterpene, has been shown to promote autophagy and attenuate sepsis-induced organ injury, yet its role in mitophagy-mediated cardioprotection remains unclear. Here, we evaluated the effects of oral BA treatment (25 mg/kg, 5 days) on lipopolysaccharide (LPS)-induced cardiac injury in male Sprague-Dawley rats. BA significantly improved cardiac function, reduced myocardial injury markers (cardiac troponin I, creatine kinase-MB), and suppressed inflammatory (tumor necrosis factor-α, interleukin-1β, myeloperoxidase activity) and oxidative responses in LPS-induced sepsis. Moreover, BA improved cardiac mitochondrial function by enhancing respiratory chain complex activity and ATP synthesis while limiting the opening of mitochondrial permeability transition pore and loss of mitochondrial membrane potential in LPS-challenged rats. Western blot and immunofluorescence analyses showed that BA enhanced PTEN-induced putative kinase 1 (PINK1)/Parkin-initiated mitophagy and suppressed BNIP3 (Bcl-2/adenovirus E1B 19 kDa interacting protein 3) expression in LPS-challenged rat hearts. Importantly, these cardioprotective effects of BA were abrogated by the mitophagy inhibitor Mdivi-1. Collectively, these results indicate that BA alleviates cardiac injury in LPS-induced sepsis by upregulating PINK1/Parkin to facilitate mitophagy and suppressing BNIP3 signaling.