651ActaPhysiologicaSinica,October25,2007,59(5):651-659http://www.actaps.com.cnReceived2007-07-20Accepted2007-08-29ThisworkwassupportedbytheNationalScienceFundationofChinaforOutstandingYoungInvestigators(No.30625033),theNationalNaturalScienceFoundationofChina(No.30471923,30500577),andtheNationalBasicResearchDevelopmentProgramofChina(No.2007CB512106).*Correspondingauthor.GAOFeng:Tel:+86-29-84776423;Fax:+86-29-84776423;E-mail:fgao@fmmu.edu.cn;WANGHai-Chang:Tel:+86-29-84773469;Fax:+86-29-84773469;E-mail:wanghc@fmmu.edu.cnInsulinprotectsisolatedheartsfromischemia/reperfusioninjury:cross-talkbetweenPI3-K/AktandJNKsLIUHai-Tao1,ZHANGHai-Feng2,SIRui1,ZHANGQuan-Jiang2,ZHANGKun-Ru2,GUOWen-Yi1,WANGHai-Chang1,*,GAOFeng2,*1DepartmentofCardiology,XijingHospital;2DepartmentofPhysiology,theFourthMilitaryMedicalUniversity,Xi’an710032,ChinaAbstract:Ourpreviousresultshavedemonstratedthatinsulinreducesmyocardialischemia/reperfusion(MI/R)injuryandincreasesthepostischemicmyocardialfunctionsviaactivatingthecellularsurvivalsignaling,i.e.,phosphatidylinositol3-kinase(PI3-K)-Akt-endothelialnitricoxidesynthase(eNOS)-nitricoxide(NO)cascade.However,itremainslargelycontroversialwhetherc-JunNH2-terminalkinase(JNK)isinvolvedintheeffectsofinsulinonMI/Rinjury.Therefore,theaimsofthepresentstudyweretoinvestigatetheroleofJNK,especiallythecross-talkbetweenJNKandpreviouslyexpatiatedAktsignaling,intheprotectiveeffectofinsulinonI/Rmyocardium.IsolatedheartsfromadultSprague-Dawleyratsweresubjectedto30minofregionalischemiaandfollowedby2or4hofreperfusion(n=6).TheheartswerepretreatedwithPI3-KinhibitorLY294002,orphosphorylated-JNKinhibitorSP600125,respectively,thenperfusedretrogradelywithinsulin,andthemechanicalfunctionsofhearts,includingtheheartrate(HR),leftventriculardevelopedpressure(LVDP)andinstantaneousfirstderivationofleftventricularpressure(±LVdp/dtmax)weremeasured.Attheendofreperfusion,theinfarctsize(IS)andapoptoticindex(AI)wereexamined.MI/Rcausedsignificantcardiacdysfunctionandmyocardialapoptosis(strongTUNEL-positivestaining).Comparedwiththecontrolgroup,insulintreatmentinMI/RratsexertedprotectiveeffectsasevidencedbyreducedmyocardialIS[(28.9±2.0)%vs(45.0±4.0)%,n=6,P<0.01],inhibitedcardiomyocyteapoptosis[decreasedAI:(16.0±0.7)%vs(27.6±1.3)%,n=6,P<0.01]andimprovedrecoveryofcardiacsystolic/diastolicfunction(includingLVDPand±LVdp/dtmax)attheendofreperfusion.Moreover,insulinresultedin1.7-foldand1.5-foldincreasesinAktandJNKphosphorylationinI/Rmyocardium,respectively(n=6,P<0.05).InhibitionofAktactivationwithLY294002abolished,andinhibitionofJNKactivationwithSP600125enhancedthecardioprotectionbyinsulin,respectively.AndtheabolishmentbyLY294002couldbepartlyconvertedbySP600125pretreatment.Inaddition,SP600125alsodecreasedtheAktphosphorylation(n=6,P<0.05).TheseresultsdemonstratethatinsulinsimultaneouslyactivatesbothAktandJNK,andthelatterfurtherincreasesthephosphorylationofAktwhichattenuatesMI/Rinjuryandimprovesheartfunction;thiscross-talkbetweenAktandJNKintheinsulinsignalingisinvolvedininsulin-inducedcardioprotectiveeffect.Keywords:ischemia/reperfusioninjury;insulin;apoptosis;Akt;JNK;cross-talk胰岛素保护缺血/再灌注心脏：PI3-K/Akt和JNKs信号通路间的交互作用刘海涛1，张海锋2，司瑞1，张全江2，张昆茹2，郭文仪1，王海昌1,*，高峰2,*第四军医大学1西京医院心血管内科；2生理学教研室，西安710032摘要：我们前期研究表明胰岛素可激活细...
