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

ObjectiveIschemia reperfusion injury is a major pathophysiologic mechanism leading to mypcardial dysfunction after myocardial infarction or cardiac surgery.It is necessary to find effective methods to limit ischemia reperfusion injury.Ischemic preconditioning and postconditioning could reducemycardial infarct size,limited tissue edema and inflammation responses, however the widespread use of Post in the clinical situation is likely to be limited by its invasive nature and is restricted to cardiac surgery and interventional therapy.Several studies have demonstrated that bradykinin when administered at the time of reperfusion could mimic ischaemic postconditioning reduce myocardial infarct size through the activation of the PI3K-Akt pathway.But the machenism of bradykinin postconditioning induced protectiong is not fully understood. JAK2-STAT3 pathway took part in a wide range of distinct cellular processes,including stress,proloferation,differentiation and apoptosis.It has been confirmed that JAK2-STAT3 pathway play an essential roles in ischemia reperfusion injury and ischemia postconditioning. The present study was designed to determine whether bradykinin postconditioning is protective against myocardial infarction and myocardial apoptosis after ischemia-reperfusion injury on rats, and to explore its protective mechanisms.Methods136 healthy male wistar rats(230g-280g) were randomly divided into five groups.(1) sham group,place suture under the coronary artery,but don't occlude the artery.(2)ischemia-reperfusion group,ischemia 30min and reperfusion 10min,120min or 24hours without additional intervention.(3) bradykinin postconditioning group,after 30min ischemia,the rats were treated with bradykinin at start of reperfusion.Then the rats were reperfused 10min,120min or 24hours.(4) bradykinin postconditioning+AG490 group,5 minutes before reperfusion,rats were treated with AG490,followed by bradykinin postconditioning and 10min,120min or 24hours reperfusion.(5) bradykinin postconditioning+wortmannin group,5 minutes before reperfusion,rats were treated with wortmannin,followed by bradykinin postconditioning and 10min,120min or 24hours reperfusion.TTC staining was useed to measure myocardial infarct size.Apoptotic index of cardiomyocyte was detected by TUNEL.Western-blot was used to detect the phosphorylated STAT3 and phosphorylated Akt levels.ResultsMyocardial apoptosis at 24 hours after reperfusion was significant increased as compared to that 2 hours after reperfusion. Bradykinin postconditioning significantly limited infarct size and myocardial apoptosis at 2 hours after reperfusion,decreased myocardial apoptosis at 24 hours after reperfusion,and increased phosphorylation of both STAT3 and Akt. AG490,a selective inhibitor of JAC2,inhibit cardioprotective effect of bradykinin postconditioning,and decrease level of phosphorylated Akt. Wortmanin, a selective inhibitor of Akt, do not effect level of phosphorylated STAT3.Conclusions1.Myocardial apoptosis is a mechanism of long term reperfusion injury.2.Bradykinin postconditioning can mimic the cardioprotective effect of ischaemic postconditioning. Bradykinin postconditioning limit myocardial infarct size and apoptosis at 2 hours after reperfusion.The anti-apoptosis effect of bradykinin postconditioning lasted over 24 hour after reperfusion.The mechanism of long term and acute cardioprotetive effects of bradykinin postconditioning needs further research.3.Cardioprotective effect of bradykinin postconditioning depends on JAK2-STAT3 pathway,and JAC2-STAT3 pathway can activate PI3K-Akt pathway.The relationship among JAC2-STAT3,PI3K-Akt pathway and myocardial ischemia reperfusion injury warrant futher study.