Essential Role of TGF-βSmad Pathway on Statin Dependent Vascular Smooth Muscle Cell Regulation 英文参考文献.docVIP

EssentialRoleofTGF-b/SmadPathwayonStatin DependentVascularSmoothMuscleCellRegulation JuanRodr?′guez-Vita1,EvaSa′nchez-Gala′n2,BeatrizSantamar?′a3,ElsaSa′nchez-Lo′pez1 ,Raquel Rodrigues-D?′ez1,Lu?′sMiguelBlanco-Colio2,Jesu′sEgido2,AlbertoOrtiz3,MartaRuiz-Ortega1* 1Cellular Biology in Renal Diseases Laboratory, Fundacio′n Jime′nez D?′az, Universidad Auto′noma Madrid, Madrid, Spain, 2Vascular Research Laboratory, Fundacio′n Jime′nezD?′az,UniversidadAuto′nomaMadrid,Madrid,Spain,3DialysisUnit,Fundacio′nJime′nezD?′az,UniversidadAuto′nomaMadrid,Madrid,Spain Abstract Background:The3-hydroxy-3-methylglutarylCoAreductaseinhibitors(alsocalledstatins)exertprovenbeneficialeffectson cardiovasculardiseases.RecentdatasuggestaprotectiveroleforTransformingGrowthFactor-b(TGF-b)inatherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies abouttheeffectofstatinsonTGF-b/Smadpathwayinatherosclerosisandvascularcells. Methodology:Inculturedvascularsmoothmusclecells(VSMCs)statinsenhancedSmadpathwayactivationcausedbyTGF- b.Inaddition,statinsupregulatedTGF-breceptortypeII(TRII),andincreasedTGF-bsynthesisandTGF-b/Smad-dependent actions.Inthis sense,statins, through Smad activation,renderVSMCs moresusceptible toTGF-binducedapoptosis and increasedTGF-b-mediatedECMproduction.Itiswelldocumentedthathighdosesofstatinsinduceapoptosisincultured VSMCinthepresenceofserum;howevertheprecisemechanismofthiseffectremainstobeelucidated.Wehavefoundthat statins-induced apoptosis was mediated by TGF-b/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylationandTRIIoverexpression,associatedtoelevatedECMdepositionintheVSMCswithinatheromaplaques, whileapoptosiswasnotdetected. Conclu