Role of JNK and p38MAPK signaling pathways in reduction of ischemia-reperfusion injury by morphine preconditioning in rats with heart failure

Objective To evaluate the role of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways in reduction of ischemia-reperfusion (I/R) injury by morphine preconditioning in the rats with heart failure. Methods Adult male Sprague-Dawley rats, weighing 200-230 g, in which doxorubicin 2 mg/kg was injected via the tail vein once a week for 6 consecutive weeks to induce chronic heart failure, were studied.At the end of 8th week, 45 rats with chronic heart failure were randomly divided into 5 groups (n=9 each) using a random number table: sham operation group (group S), group I/R, morphine preconditioning group (group MPC), SP600125 (JNK inhibitor) + morphine preconditioning group (group MSP)and SB203580 (p38MAPK inhibitor) + morphine preconditioning group (group MSB). Myocardial I/R was induced by 30 min occlusion of the anterior descending branch of the coronary artery followed by 120 min reperfusion in each group except group S. In group MPC, the rats were subjected to 3 cycles of 5-min infusion of 0.1 mg/kg morphine via the femoral vein at 5 min interval before ischemia.In MSP and MSB groups, SP600125 0.5 mg/kg and SB203580 0.2 mg/kg were injected via the femoral vein, respectively, at 10 min before morphine preconditioning.The animals were sacrificed at 120 min of reperfusion, and the myocardial specimens were obtained for determination of the total areas of right and left ventricles (LV+ RV), area at risk (AAR), infarct size (IS), and expression of PKC δ in myocardial tissues (by immunohistochemistry), and IS/AAR ratio was calculated. Results There was no significant difference in LV+ RV and AAR between the five groups (P>0.05). Compared with group S, IS and IS/AAR were significantly increased, and the expression of PKC δ was up-regulated in I/R and MSB groups(P 0.05). Conclusion Activation of p38MAPK signaling pathway is involved in reduction of myocardial I/R injury by morphine preconditioning, and the mechanism is related to down-regulation of PKC δ expression in rats with heart failure; JNK signaling pathway is not involved in this process. Key words: JNK mitogen-activated protein kinases; p38 mitogen-activated protein kinases; Morphine; Ischemic preconditioning; Heart failure; Myocardial reperfusion injury