Motor protein KIF5B inhibition as a novel strategy of controlled reperfusion against myocardial ischemia/reperfusion injury.

Metabolic dysregulation triggered by nutrient influx at reperfusion onset induces reactive oxygen species (ROS) burst and cellular injury, contributing to the detrimental effects observed in ischemia/reperfusion (I/R) injury. Thus, implementing controlled reperfusion emerges as a superior cardioprotective strategy to alleviate reperfusion injury. Kinesin KIF5B transports GLUT4- and CD36-containing vesicles to the plasma membrane, facilizing the import of glucose and fatty acids into cells, suggesting a role in controlled reperfusion. Herein, we aim to investigate its specific role in myocardial I/R injury. By genetic and pharmacological modulation of KIF5B, we investigated its role in myocardial I/R injury both in vivo and in vitro. During reperfusion, a coordinated inhibition of metabolism-related genes and KIF5B expression occurred, probably mitigating the metabolic stress encountered as a compensatory mechanism. Genetic inhibition of KIF5B using AAV9-shRNA attenuated myocardial I/R injury, as evidenced by reduced infarct size, decreased cardiac biomarkers, and reduced cell apoptosis. Additionally, KIF5B inhibition mitigated post-reperfusion oxidative stress and arrhythmias. Mechanistically, concurrent decrease in CD36 membrane translocation following KIF5B ablation post-reperfusion was confirmed by immunofluorescence double staining, and siRNA knockdown of Kif5b inhibited fatty acids uptake in isolated primary neonatal rat cardiomyocytes. Intraperitoneal administration of rose bengal lactone (RBL, 1 mg/kg), a selective inhibitor of KIF5B, was shown to confer cardioprotective effects against myocardial I/R injury. Our findings demonstrate that the inhibition of KIF5B, as a novel strategy of controlled reperfusion, provides cardioprotection against myocardial I/R injury, and highlights the clinical potential of its inhibitor, RBL, to ameliorate reperfusion injury.