Role Of JAK2-STAT3 Pathway In Cardioprotective Effect Of Ischemic Postconditioning

Objective Ischemia reperfusion injury is a major pathophysiologic mechanism leading to myocardial dysfunction after myocardial infarction or cardiac surgery. Recent studies even showed that reperfusion injury has long term cardioprotective effect.It is necessary to find effective methods to limit ischemia reperfusion injury. Postconditioning is composed of brief cycles of reperfusion and ischemia at the onset of reperfusion,which could reduced myocardial infarct size,limited tissue edema and inflammation responses.Subsequent studies showed that postconditioning is cardioprotective in patients undergoing PCI for acute myocardial infarction or undergoing cardiac surgery for tetralogy of Fallot.But the machenism of postconditioning induced protection is not fully understood.By regulate the transcription;JAK2-STAT3 pathway took part in a wide range of distinct cellular processes,including stress,proliferation,differentiation and apoptosis.It has been confirmed that JAK2-STAT3 pathway play an essential roles in ischemia reperfusion injury and ischemia preconditioning.The present study was designed to demonstrate 1.long term effect of reperfusion injury;2,acute and longterm cardioprotective effect of postconditioning on reperfusion injury;3,role of JAK2-STAT3 pathway in anti-apoptosis effect of postconditioning.Methods One hundred and twenty eight healthy adult male wistar rats were divided into four groups.1) sham group,place suture under the coronary artery,but don't occlude the artery.2) ischemia-reperfusion injury group,ischemia 30min and reperfusion 10min,120min or 24 hours without additional intervention.3) postconditioning(Post) group,after 30min ischemia,the rat was comprised 3 cycles of 10 seconds of reperfusion followed by 10 seconds ischemia,then reperfused 10min, 120min or 24 hours.4) postconditioning+AG490(Post+AG490) group,5 minutes before reperfusion,rats were treated with AG490,followed by postconditioning and 10min,120min or 24 hours reperfusion.Infarct size at 2 hours after reperfusion was determined by TTC staining.TUNEL analysis was used to detect the apoptosis at 2 and 24 hours after reperfusion.Western-blot was used to detect the phosphorylated STAT3 and phosphorylated Akt levels.Results Myocardial apoptosis at 24 hours after reperfusion was significant increased as compared to that 2 hours after reperfusion(24h 84±4 vs 2h 73±6,P＜0.05). Postconditioning significantly limited infarct size and myocardial apoptosis at 2 hours after reperfusion(infarct size:I/R group 58±5.3%vs Post group 38±4.3%,P＜0.05;myocardial apoptosis:I/R group 73±6 vs Post group 40±4,P＜0.05),decreased myocardial apoptosis at 24 hours after reperfusion(I/R group 82±4 vs Post group 63±4,P＜0.05),and increased phosphorylation of both STAT3 and Akt.AG490,a selective inhibitor of JAK2,abolished the anti-apoptosis effect of postconditioning (2h Post group 40±4 vs Post+AG490 group 70±3,24h Post group 63±4 vs 84±4,P＜0.05),and deceased level of phosphorylated Akt.Conclusions 1)Myocardial apoptosis is a mechanism of long term reperfusion injury. 2) Posconditioning limit myocardial infarct size and apoptosis at 2 hours after reperfusion.The anti-apoptosis effect of postconditioning lasted over 24 hour after reperfusion.The relationship of long term and acute cardioprotective effects of potconditioning needs further research.3) Cardioprotective effect of postconditioning depends onJAK2-STAT3 pathway,and subsequently activatePI3K/Akt pathway.The relationship among JAK2-STAT3,PI3K/Akt pathway and myocardial apoptosis warrant further study.