Protective effects and mechanism of penehyclidine hydrochloride on myocardial ischemia-reperfusion injury in mice
OBJECTIVE To investigate the protective effects and potential mechanism of penehyclidine hydrochloride(PHC)on myocardial ischemia-reperfusion(I/R)injury in mice through the macrophage migration inhibitory factor(MIF)/adenosine monophosphate-activated protein kinase(AMPK)signaling pathways.METHODS Male C57BL/6 mice were randomly divided into sham operation group,I/R group,I/R+PHC group(PHC 20 μg/kg),I/R+ISO-1 group(MIF inhibitor 35 mg/kg),I/R+PHC+ISO-1 group(with the same dosage as each single drug group),with 8 mice in each group.Except for the sham operation group,the myocardial I/R injury model was prepared by coronary artery ligation.Thirty minutes before ligation,mice in each drug group were injected with 1 mL of the corresponding drug solution through the tail vein.After 120 min of reperfusion,the levels of cardiac function indexes[heart rate,stroke volume,ejection fraction,cardiac output,left ventricular posterior wall thickness in systole(LVPWs),left ventricular posterior wall thickness in diastole(LVPWd)],serum inflammatory factors[interleukin-6(IL-6),IL-10,tumor necrosis factor-α(TNF-α)]in mice were detected in each group;the pathological changes and ultrastructure of myocardial tissue were observed,and the protein expressions of B cell lymphoma-2(Bcl-2),phosphorylated AMPKα(p-AMPKα)and MIF in myocardial tissue were detected.RESULTS Compared with the sham operation group,the myocardial cells in the I/R group were loosely arranged,with severe infiltration of inflammatory cells and obvious mitochondrial damage.Serum levels of IL-6 and TNF-α and protein expression of p-AMPKα in myocardial tissue were significantly increased or upregulated,while heart rate,stroke volume,ejection fraction,cardiac output,LVPWd and serum level of IL-10 were significantly decreased(P＜0.05).Compared with the I/R group,the myocardial tissue lesions in the I/R+PHC group were alleviated;serum levels of IL-6 and TNF-α were decreased significantly,while heart rate,stroke volume,ejection fraction,cardiac output,LVPWs,LVPWd,serum level of IL-10,and protein expressions of Bcl-2,p-AMPKα and MIF in myocardial tissue were significantly increased or upregulated(P＜0.05).However,myocardial tissue lesions of mice in the I/R+ISO-1 group worsened,with most quantitative indicators significantly deteriorating(P＜0.05);MIF inhibitor could generally reverse the protective effect of PHC on I/R mice(P＜0.05).CONCLUSIONS PHC can improve cardiac function,reduce myocardial inflammation,and restore the ultrastructure of myocardial tissue in I/R mice.These effects may be related to the activation of the MIF/AMPK signaling pathway.
万方数据
维普
