Rac Inhibition Reverses the Phenotype of Fibrotic Fibroblasts 英文参考文献.docVIP

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Rac Inhibition Reverses the Phenotype of Fibrotic Fibroblasts 英文参考文献.doc

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Rac Inhibition Reverses the Phenotype of Fibrotic Fibroblasts 英文参考文献

RacInhibitionReversesthePhenotypeofFibrotic Fibroblasts XuShi-wen1,ShangxiLiu2,MarkEastwood3,SonaliSonnylal4,ChristopherP.Denton1,DavidJ Abraham1.,AndrewLeask2. * 1Centre for Rheumatology, Department of Medicine, University College London (Royal Free Campus), London, United Kingdom, 2The Canadian Institute of Health ResearchGroupinSkeletalDevelopmentandRemodeling,DivisionofOralBiologyandDepartmentofPhysiologyandPharmacology,SchulichSchoolofMedicineand Dentistry,UniversityofWesternOntario,London,Ontario,Canada,3SchoolofBiosciences,UniversityofWestminster,London,UnitedKingdom,4UniversityofTexas,M. D.AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica Abstract Background: Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrixandproducea2smoothmuscleactin(a-SMA),typeIcollagenandCCN2(connectivetissuegrowthfactor,CTGF).The basisforthisphenomenonispoorlyunderstood,andisanecessaryprerequisitefordevelopingnovel,rationalanti-fibrotic strategies. MethodsandFindings:Comparedtohealthyskinfibroblasts,dermalfibroblastsculturedfromlesionalareasofscleroderma (SSc) patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesionalSScfibroblasts.NSC23766causedadecreaseinmigrationonandcontractionofmatrix,anda2SMA,typeIcollagen andCCN2mRNAandproteinexpression.SScfibroblastspossessedelevatedAktphosphorylation,whichwasalsoblocked by NSC23766. Overexpression of rac1 in normal fibroblasts induced matrix contraction and a2SMA, type I collagen and CCN2mRNAandproteinexpression.Rac1activitywasblockedbyPI3kinase/Aktinhibition.Basalfibroblastactivitywasnot affectedbyNSC23766. Conclusion:RacinhibitionmaybeconsideredasanoveltreatmentforthefibrosisobservedinSSc. Citation:Shi-wenX,LiuS,EastwoodM,SonnylalS,DentonCP,etal.(2009)RacInhibitionReversesthePhenoty