Redox-Induced Src Kinase and Caveolin-1 Signaling in TGF-β1-Initiated SMAD23 Activation and PAI-1 Expression 英文参考文献.docVIP

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Redox-Induced Src Kinase and Caveolin-1 Signaling in TGF-β1-Initiated SMAD23 Activation and PAI-1 Expression 英文参考文献.doc

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Redox-Induced Src Kinase and Caveolin-1 Signaling in TGF-β1-Initiated SMAD23 Activation and PAI-1 Expression 英文参考文献

Redox-InducedSrcKinaseandCaveolin-1Signalingin TGF-b1-InitiatedSMAD2/3ActivationandPAI-1 Expression RohanSamarakoon1,SubhanirS.Chitnis1,StephenP.Higgins1,CraigE.Higgins1,JoanC.Krepinsky2, PaulJ.Higgins1* 1Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York, United States of America, 2Division of Nephrology, McMaster University, Hamilton,Ontario,Canada Abstract Background: Plasminogen activator inhibitor-1 (PAI-1), a major regulator of the plasmin-based pericellular proteolytic cascade,issignificantlyincreasedinhumanarterialplaquescontributingtovesselfibrosis,arteriosclerosisandthrombosis, particularly in the context of elevated tissue TGF-b1. Identification of molecular events underlying to PAI-1 induction in responsetoTGF-b1mayyieldnoveltargetsforthetherapyofcardiovasculardisease. PrincipalFindings:Reactiveoxygenspeciesaregeneratedwithin5minutesafteradditionofTGF-b1toquiescentvascular smoothmusclecells(VSMCs)resultinginpp60c-srcactivationandPAI-1expression.TGF-b1-stimulatedSrckinasesignaling sustained the duration (but not the initiation) of SMAD3 phosphorylation in VSMC by reducing the levels of PPM1A, a recentlyidentifiedC-terminalSMAD2/3phosphatase,therebymaintainingSMAD2/3inanactivestatewithretentionofPAI- 1transcription.ThemarkedlyincreasedPPM1AlevelsintripleSrckinase(c-Src,Yes,Fyn)-nullfibroblastsareconsistentwith reductions in both SMAD3 phosphorylation and PAI-1 expression in response to TGF-b1 compared to wild-type cells. ActivationoftheRho-ROCKpathwaywasmediatedbySrckinasesandrequiredforPAI-1inductioninTGF-b1-stimulated VSMCs.InhibitionofRho-ROCKsignalingblockedtheTGF-b1-mediateddecreaseinnuclearPPM1Acontentandeffectively attenuatedPAI-1expression.TGF-b1-inducedPAI-1expressionwasundetectableincaveolin-1-nullcells,correlatingwiththe reduced Rho-GTP loading and SMAD2/3 phosphorylation evident in TGF-b1-treated caveolin-1-deficient cells relative to theirwild-type counterparts. Src kinases,moreover,werecritical upstream e