Role of JAK2-STAT3 signaling pathway in sevoflurane postconditioning-induced inhibition of mPTP opening during myocardial ischemia-reperfusion in rats

Abstract

Objective To evaluate the role of Janus kinase 2-signal transducer and activator of transcription 3(JAK2-STAT3)signaling pathway in sevoflurane postconditioning-induced inhibition of mitochondrial permeability transition pore(mPTP)opening during myocardial ischemia-reperfusion(I/R)in rats. Methods Sixty pathogen-free healthy male Sprague-Dawley rats, weighing 250-300 g, were divided into 4 groups(n=15 each)using a random number table: I/R group, sevoflurane postconditioning group(group SP), AG-490 group(group AG)and sevoflurane postconditioning plus AG-490 group(group SP+ AG). Myocardial I/R was induced by 30 min ligation of the left anterior descending branch of coronary artery followed by 120 min reperfusion.In group SP, 2.8% sevoflurane was inhaled for 15 min starting from 2 min before reperfusion.JAK2 inhibitor AG-490 3 mg/kg was intravenously injected at 10 min before reperfusion in group AG.In group SP+ AG, AG-490 3 mg/kg was intravenously injected at 10 min before reperfusion, and 2.8% sevoflurane was inhaled for 15 min starting from 2 min before reperfusion.At 15 min of reperfusion, 5 rats were sacrificed and myocardial specimens were obtained for determination of the expression of JAK2, phosphorylated JAK2(p-JAK2), STAT3 and phosphorylated STAT3(p-STAT3)in myocardial tissues by Western blot.The ratios of p-JAK2 to JAK2 expression(p-JAK2/JAK2)and p-STAT3 to STAT3 expression(p-STAT3/STAT3)were calculated.Five rats were sacrificed at the end of reperfusion for measurement of myocardial infarct size.The left 5 rats were selected and sacrificed, myocardial specimens were obtained, and the opening of mPTP was detected by a calcein-cobalt quenching method. Results Compared with group I/R, the myocardial infarct size and mPTP opening were significantly decreased, and JAK2/p-JAK2 and STAT3/p-STAT3 were increased in group SP(P 0.05). Compared with group SP, the myocardial infarct size was significantly enlarged, the extent of mPTP opening was aggravated, and JAK2/p-JAK2 and STAT3/p-STAT3 were decreased in SP+ AG and AG groups(P<0.05). Conclusion The mechanism by which sevoflurane postconditioning inhibits the opening of mPTP during myocardial I/R is related to activation of JAK2-STAT3 signaling pathway in rats. Key words: Aesthetics, inhalation; Janus kinase 2; STAT3 transcription factor; Mitochondrial membrane transport proteins; Myocardial reperfusion injury; Ischemic postconditioning