LAUSR

ABSTRACT Penehyclidine hydrochloride (PHC) preconditioning can alleviate myocardial ischemia/reperfusion (I/R) injury and inhibits the upregulation of voltage‐dependent anion channel 1 (VDAC1) during I/R. To validate that VDAC1 is a bona fide target of PHC for the protection against myocardial I/R injury, VDAC1 expression construct was delivered by lentiviruses into rat left ventricular myocardium before PHC preconditioning and myocardial I/R. Overexpression of VDAC1 exacerbated cardiac dysfunction and myocardial injury following I/R, and abolished the cardioprotective effect of PHC during I/R injury. Moreover, VDAC1 overexpression with myocardial I/R further increased cytochrome c release from mitochondria to cytoplasm, elevated the levels of cleaved caspase‐3 and Bax, and decreased the level of Bcl‐2 as compared with I/R alone, and PHC‐mediated inhibition of mitochondria‐dependent apoptosis during myocardial I/R was abolished by VDAC1 overexpression. In addition, VDAC1 was overexpressed in H9c2 cardiomyocytes undergoing anoxia/reoxygenation (A/R) with or without PHC pretreatment. The in vitro results showed that overexpression of VDAC1 further reduced mitochondrial membrane potential, increased mitochondrial membrane permeability and enhanced mitochondria‐dependent apoptosis in H9c2 cells after A/R, and VDAC1 overexpression abrogated the protective effect of PHC on the mitochondrial function and integrity during A/R. In conclusion, exogenous overexpression of VDAC1 during myocardial I/R inhibits the cardioprotective effects of PHC. These effects may be associated with the suppression of VDAC1 expression.