Cholecystokinin-mediated pharmacological preconditioning effects on ischemic rat hearts: Possible signaling pathways

Background. Cholecystokinin (CCK-8) has been shown to exhibit pharmacological preconditioning and cardioprotective effects. However, the molecular mechanisms involved in CCK-8-induced pharmacological preconditioning have not yet been clarified. Objectives. The current study explored the molecular mechanisms involved in CCK-8-mediated pharmacological preconditioning effects on ischemic rat hearts. Materials and methods. Pharmacological preconditioning was induced in male Wistar rats by administration of CCK-8 (20 mu g/kg) 24 h before heart isolation. The PI3K inhibitor LY294002 (10 mg/kg and 20 mg/kg) and the HIF-1 alpha inhibitor YC-1 (1 mg/kg and 2 mg/kg) were administered 30 min before the administration of CCK-8. The hearts were subjected to ischemia-reperfusion (IR) injury using a Langendorff apparatus. Myocardial injury was quantified by measuring the release of LDH-1, CK-MB and cTnT. The levels of HIF-1 alpha and p-Akt expression and the ratio of p-GSK-3 beta/GSK-3 beta, were assessed in the heart homogenates. Results. Pharmacological preconditioning with CCK-8 reduced IR-induced increases in the release of LDH, CK-MB and cTnT. Moreover, it restored the expression of HIF-1 alpha and p-Akt, and the p-GSK-3 beta/GSK-3 beta ratio. However, administration of LY294002 or YC-1 with CCK-8 significantly abolished the cardioprotective effects of pharmacological preconditioning. The PI3K and HIF-1 alpha inhibitors also abolished the effects of CCK-8 preconditioning on HIF-1 alpha, p-Akt and p-GSK-3 beta/GSK-3 beta. Conclusions. Based on these findings, it may be concluded that the molecular mechanisms participating in CCK-8-induced pharmacological preconditioning involve HIF-1 alpha, PI3K, Akt, and GSK-3 beta signaling pathways.