Poliovirus Receptor–Related 2 Aránzazu Rossignoli.pdf

该【Poliovirus Receptor–Related 2 Aránzazu Rossignoli 】是由【彩屏】上传分享，文档一共【21】页，该文档可以免费在线阅读，需要了解更多关于【Poliovirus Receptor–Related 2 Aránzazu Rossignoli 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。:..OriginalResearchPoliovirusReceptor–Related2ACholesterol-ResponsiveGeneAffectingAtherosclerosisDevelopmentbyModulatingLeukocyteMigrationAránzazuRossignoli,Ming-MeiShang,HannaGladh,ChristineMoessinger,HassanForoughiAsl,HusainAhammadTalukdar,OscarFranzén,SteffenMueller,?rkegren,*ErikaFolestad,*JosefinSkogsbergObjective—Recently,poliovirusreceptor–related2(Pvrl2)emergedasatopgeneinaglobalgeneexpressionstudyaimingtodetectplasmacholesterol–,,—Pvrl2-deficientmicebredontoanatherosclerosis-pronebackground(Pvrl2?/?Ldlr?/?Apob100/100)paredwithlittermatecontrols(Pvrl2+/+Ldlr?/?Apob100/100).Pvrl2?/?Ldlr?/?Apob100/100micealsoshoweda49%,://atvb./andmice,,—PVRL2isaplasmacholesterol–responsivegeneactingatendothelialsitesofvascularinflammationthatcouldpotentiallybeanewtherapeutictargetforatherosclerosispreventionthroughitssuggestedtransendothelialmigrationofleukocytesmodulatingactivity.(;37:00-:.308715.)KeyWords:adherensjunctions?atherosclerosis?cholesterol?coronaryarterydisease?inflammationbyguestonJanuary9,2017ardiovasculardiseases(CVDs)remaintheleadingcauseTEMLisacentral,continuousinflammatorystepofath--However,targetingTEMLisnottrivialbecausethispathwaytionoflow-densitylipoproteins(LDLs),endothelialactiva-isalsocrucialforinflammationandimmuneresponsesintion,transendothelialmigrationofleukocytes(TEML),,generationoffoamcellsinitiatingtheformationofadvancedsideeffects,suchasopportunisticinfections,-loweringdrugs,suchHowever,targetingTEMLinamoreatherosclerosis-specificasstatins,,4BesidesandresponsivetoCVDriskfactors,suchasplasmaLDL-thedirecteffectsofstatins,-inflammatorypropertiesInTEML,,–related2(Pvrl2)hasnotbeenrecognizedasoneofcholesterolandinflammationareneededforpreventingdis-thetraditionalTEMLgenes,butitfunctionsasacelladhe-easedevelopmentsuggestingthatdual-,,6intheatheroscleroticarterialwallbecauseoneofthegenesReceivedon:June14,2016;eptedon:December19,,DepartmentofMedicalBiochemistryandBiophysics(.,.,.,.,.,.,.,.)andputationalMedicine,DepartmentofMedicine(M.-.),KarolinskaInstitutet,Stockholm,Sweden;icsandGenomicSciences,InstituteofGenomicsandMultiscaleBiology,IcahnSchoolofMedicineatMountSinai,NewYork,NY(.,.);andDepartmentoficsandMicrobiology,StonyBrookUniversity,NewYork,NY(.).*-onlyDataSupplementisavailablewiththisarticleathttp://atvb./lookup/suppl/doi:.308715/-/ánzazuRossignoli,DivisionofVascularBiology,DepartmentofMedicalBiochemistryandBiophysics,KarolinskaInstitutet,17177Stockholm,-mailErika.******@.******@?2017AmericanHeartAssociation,://:.3087151:..2ArteriosclerThrombVascBiolMarch2017phenotypes,carotidintima-mediathicknessandcoronaryNonstandardAbbreviationandAcronymsarterydisease(CAD).19,20Todate,littleisknownaboutCADcoronaryarterydiseasePVRL2inatherosclerosisexceptforarecentstudyinmouse,CVDcardiovasculardiseasewherePvrl2expressioninprelesionaorticendotheliumwasLDLlow--PCLplasmacholesterolloweringgestaroleforPVRL2inpromotingleukocytediapedesisdur-,23PVRL2poliovirusreceptor-related2STAGEStockholmAtherosclerosisGeneExpressionGivenitsplasmacholesterolresponsivenessanditssug-TEMLtransendothelialmigrationofleukocytesgestedinvolvementinTEML,wewantedtodeterminewhetherPVRL2maybeasuitabledrugtargettopreventath-,theatherogenicroleofPVRL2andTEMLwasinvestigatedinPvrl2-deficientmarkedlydownregulatedinresponsetoplasmacholesterolmicebredontoanatherosclerosis-pronebackgroundwithalowering(PCL)inatherosclerosis-pronemicewithhuman-human-likeplasmaLDLprofile(Pvrl2?/?Ldlr?/?Apob100/100)likeplasmacholesterolprofile,Ldlr?/?Apob100/100Mttpflox/flox9,10andcross-validatedinwell-characterizedCADpatientsusingMx1--,orNECTIN2,encodesasingle-passtypeImem-MaterialsandMethodsbraneglycoproteinthat,astheothernectinmembers,bindsMaterialsandMethodsareavailableintheonline-–bindingpro-tein,AF-6/,regulate,andinteractwithjunctionproteinssuchasResultshttp://atvb./E-cadherinatadherensjunctionsandJAM-Aattightjunc-,epithe-ExpressionDuringAtherosclerosisProgressionlial,endothelial,,wehaveusedawhole-genomeexpressionprofil-Besidesitswell-knownroleasanentryreceptorforviruses,13ingtoidentifyplasmacholesterol–responsivegenesdrivingithasalsobeenshowntobeinvolvedinbreastandovarianatherosclerosisregressionatdifferentstagesindiseasedevel-cancers14andAlzheimer’sdisease,15,16aswellasbeinganopmentinLdlr?/?Apob100/100Mttpflox/floxMx1-,10Pvrl2organizerofSertolicell–(week30)andmature(week40),,closetotheatheroscleroticarterialwallexpressionofPvrl2decreasedbyapolipoproteingenesAPOE,APOC1,APOC2,%and25%afterPCLinearlyandmaturelesions,respec-ThislocushaspreviouslybeenassociatedwiththeCVDtively(Figure1A).–related2(Pvrl2)responsivenessandleukocyteexpressionduringatherosclerosisprogressioninLdlr?/?Apob100/100Mttpflox/floxMx1-,RelativePvrl2expressionintheaorticarchofearly(30-wk-old)andmature(40-wk-old)femalemicelesionsbeforeplasmacholesterollowering(PCL;Ldlr?/?Apob100/100Mttpflox/floxMx1-Cre,n=4micepergroup)orafterPCL(Ldlr?/?Apob100/100MttpΔ/ΔMx1-Cre,n=4micepergroup).B,Relativeexpressionofcell-specificleukocytemarkers(normalizedaverageofCd11α,Cd16,Cd44,Cd68,andCd86;—line)andPvrl2(—line)intheaorticarchof10,20,30,40,50,and60-wk-oldmice(n=4–6micepertimepoint);andlesionareapercent(···line)duringatherosclerosisprogression(n=4–10micepertimepoint).*,statisticalsignificancefortherelativePvrl2expression;?,statisticalsignificancefortherelativeleukocyteexpression;*P<–WhitneyUtest(AandB).Dataarepresentedasmean±.:..–Related2ExpressionandPlasmaCholesterolLevelsFromPatientsintheCoronaryArteryDiseaseCohortSTAGE(StockholmAtherosclerosisGeneExpression)ExtentofAtherosclerosisExtentofAtherosclerosisTissueTotalPlasmaCHLPlasmaVLDL,CHLPlasmaLDL,CHLPlasmaHDL,,*,*,*,,,*Non-,?,,,,,?,?,?,?,,?,(r,Pvalue).Hypercholesterolemicpatients>5mmol/;CHL,cholesterol;HDL,high-densitylipoprotein;LDL,low-densitylipoprotein;Non-AAW,nonatheroscleroticarterialwall;andVLDL,verylow-densitylipoprotein.*,weassociatedTheplasmacholesterol–responsiveeffectofPVRL2,itsPVRL2expressioninthearterialwall(atheroscleroticandchangesinexpressionduringatherosclerosisprogression,andnonatherosclerotic)andbloodwithplasmacholesterollev-proposedroleinTEMLsuggestthatPVRL2mightbeasuit-DownloadedfromelsinCADpatientsfromtheSTAGEstudy(-AtherosclerosisGeneExpression).24–26TheSTAGEstudysis,weobtainedPvrl2-deficientmice(Pvrl2?/?)andcrossbredcomprisescarefullycharacterizedpatientsundergoingthemwithLdlr?/?Apob100/?/?Apob100/100micecoronaryarterybypassgraftingsurgeryfromwhichglobalhaveahuman-likeLDL-cholesterolprofileandarepronegeneexpressionprofileswereobtainedfromCAD-,triglyceride,glucoselevels,orweightathttp://atvb./arterialwallwerefoundtocorrelatewithplasmacholes-euthanize(Table2).However,after40weeks,thelesionareaterollevels:totalcholesterol(r=,P=),LDL-inpinned-outaortaswasreducedonaverage31%(P=)cholesterol(r=,P=),andveryLDL-cholesterolinPvrl2?/?Ldlr?/?Apob100/paredwithlittermatecontrols(r=,P=;Table1).Incontrast,thiscorrelation(Pvrl2+/+Ldlr?/?Apob100/100;Figure2A).wasnotfoundinthenonatheroscleroticwallorblood(ofNext,theatherogenicroleofPVRL2wasvalidatedinthenote,thegenome-wideexpressiondatafrombloodismainlyCADcohort,–26LevelsofPVRL2expressioninthederivedfromleukocytes;Table1).Takentogetherthesefind-atheroscleroticarterialwallwerefoundtocorrelatewiththebyguestonJanuary9,2017ingssuggestthatPVRL2inhumansrespondstoplasmacho-extentofcoronaryatherosclerosisinhypercholesterolemiclesterolintheactivatedendothelium,thatis,atheroscleroticpatients(Table1).,indicatingthathighplasmacholes-Next,weinvestigatedthechangesinPvrl2expressiondur-terollevelsarerequiredforPVRL2toactondiseasedevel-ingatherosclerosisprogressioninLdlr?/?Apob100/100Mttpflox/-Cremiceinwhichthedevelopmentofatherosclero-arterialwallorinblood(Table1).,10Betweenweek20and30,justbeforetherapidexpansionofatheroscleroticPvrl2DeficiencyModulateslesionsinthesemice,positionPvrl2expressionby48%(P=;Figure1B),whereNext,,theaug-inaorticrootcrosssectionsfromPvrl2?/?Ldlr?/?Apob100/100mentedexpressionofPvrl2coincidedwithanincreasedmiceandlittermatecontrols(Pvrl2+/+Ldlr?/?Apob100/100)at40expressionofmigrat