Role of PI3K/Akt signaling pathway in sufentanil postconditioning-induced reduction of myocardial ischemia-reperfusion injury in rats: the relationship with mitochondrial permeability transition pore

Objective To investigate the mechanism underlying sufentanil postconditioning-induced reduction of myocardial ischemia-reperfusion(I/R)injury in rats through evaluating the relationship between phosphatidylinositol 3-kinase/serine-threonine kinase(PI3K/Akt)signaling pathway and mitochondrial permeability transition pore(mPTP). Methods Forty-eight pathogen-free healthy male Sprague-Dawley rats, aged 3 months, weighing 250-300 g, were divided into 4 groups(n=12 each)using a random number table: sham operation group(group S), group I/R, sufentanil postconditioning group(group SP)and sufentanil postconditioning plus PI3K inhibitor wortmannin group(group SP+ W). The rats were anesthetized with 20% urethane 5 ml/kg.Myocardial I/R was induced by ligation of the anterior descending branch of left coronary artery for 30 min, followed by 120 min reperfusion.Sufentanil 1.0 μg/kg was injected via the sublingual vein at 5 min before reperfusion in SP and SP+ W groups.Wortmannin 15 μg/kg was injected via the sublingual vein at 5 min before reperfusion, and then sufentanil 1.0 μg/kg was given in group SP+ W.Blood samples were taken from the abdominal aorta at the end of reperfusion for detection of serum cardiac troponin I(cTnI)and creatine kinase-MB(CK-MB)concentrations.The rats were then sacrificed and hearts were removed for determination of cell apoptosis(by TUNEL), nicotinamide adenine dinucleotide(NAD+ )content(by spectrophotometry), and expression of phosphorylated Akt(p-Akt)in myocardial tissues(by Western blot). Apoptosis index(AI)was calculated.The myocardial mitochondria and cytoplasm were isolated for detection of the expression of cytochrome c(Cyt c)and apoptosis-inducing factor(AIF)using Western blot. Results Compared with group S, the serum cTnI and CK-MB concentrations and AI were significantly increased, the content of NAD+ was decreased, the expression of p-Akt was up-regulated, the expression of Cyt c and AIF in mitochondria was down-regulated, and the expression of Cyt c and AIF in cytoplasm was up-regulated in I/R, SP and SP+ W groups(P<0.05). Compared with group I/R, the serum cTnI and CK-MB concentrations and AI were significantly decreased, the content of NAD+ was increased, the expression of p-Akt was up-regulated, the expression of Cyt c and AIF in mitochondria was up-regulated, and the expression of Cyt c and AIF in cytoplasm was down-regulated in group SP(P<0.05). Compared with group SP, the serum cTnI and CK-MB concentrations and AI were significantly increased, the content of NAD+ was decreased, the expression of p-Akt was down-regulated, the expression of Cyt c and AIF in mitochondria was down-regulated, and the expression of Cyt c and AIF in cytoplasm was up-regulated in group SP+ W(P<0.05). Conclusion Sufentanil postconditioning can activate PI3K/Akt signaling pathway, inhibit mPTP opening, mitigate mitochondrial injury and inhibit apoptosis in cardiomyocytes, thus attenuating myocardial I/R injury in rats. Key words: 1-phosphatidlylinositol 3-kinase; Protein-serine-threonine kinase; Sufentanil; Ischemic postconditioning; Myocardial reperfusion injury; Mitochondrial permeability transition pore