Fasudil Protects the Heart against Ischemia-Reperfusion Injury by Attenuating Endoplasmic Reticulum Stress and Modulating SERCA Activity The Differential Role for PI3KAkt and JAK2STAT3 Signaling Pathways 英文参考文献.docVIP

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Fasudil Protects the Heart against Ischemia-Reperfusion Injury by Attenuating Endoplasmic Reticulum Stress and Modulating SERCA Activity The Differential Role for PI3KAkt and JAK2STAT3 Signaling Pathways 英文参考文献.doc

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Fasudil Protects the Heart against Ischemia-Reperfusion Injury by Attenuating Endoplasmic Reticulum Stress and Modulating SERCA Activity The Differential Role for PI3KAkt and JAK2STAT3 Signaling Pathways 英文参考文献

FasudilProtectstheHeartagainstIschemia-Reperfusion InjurybyAttenuatingEndoplasmicReticulumStressand ModulatingSERCAActivity:TheDifferentialRolefor PI3K/AktandJAK2/STAT3SignalingPathways YapengLi.,WeiZhu*.,JianpingTao.,PingXin,MingyaLiu,JingboLi,MengWei* DivisionofCardiology,ShanghaiSixthHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,StateKeyDisciplineDivision,Shanghai,People’sofRepublicofChina Abstract Disorderedcalciumhomeostasiscanleadtoendoplasmicreticulum(ER)stress.Ourpreviousdatashowedthattimecourse activation of ER stress contributes to time-related increase in ischemia-reperfusion (I/R) injury. However, it has not been testedwhetherPI3K/AktandJAK2/STAT3pathwaysplaydifferentialrolesinreducingERstresstoprotecttheheart.Inthe present study, using fasudil which is a specific inhibitor of ROCK, we aimed to investigate whether improved SERCA expressionandactivityaccountsforreducedERstressbyROCKinhibition,specificallywhetherPI3K/AktandJAK2/STAT3 pathways are differentially involved in modulating SERCA activity to reduce ER stress and hence I/R injury. The results showedthatduringthereperfusionperiodfollowing45minofcoronaryligationtheinfarctsize(IS)increasedfrom3hof reperfusion (45.465.57%) to 24h reperfusion (64.2165.43, P,0.05), which was associated with ER stress dependent apoptosissignalingactivationincludingCHOP,Caspase-12andJNK(P,0.05,respectively).ThedynamicERstressactivation was also related to impaired SERCA activity at 24h of reperfusion. Administration of fasudil at 10mg/Kg significantly attenuatedROCKactivationduringreperfusionandresultedinanimprovedSERCAactivitywhichwascloselyassociated with decreases in temporal activation of ER stress and IS changes. Interestingly, while both PI3K/Akt and JAK2/STAT3 signalingpathwaysplayedequalroleintheprotectionofferedbyROCKinhibitionat3hofreperfusion,therescuedSERCA expression and activity at 24h of reperfusion by fasudil was mainly due to JAK2/STAT3 activation, in which PI3K/Akt signalingsharedmuchlessroles. C