19LDL-cholesterol versus HDL-cholesterol in the atherosclerotic plaque inflammatory resolution versus
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19LDL-cholesterol versus HDL-cholesterol in the atherosclerotic plaque inflammatory resolution versus
Ann.N.Y.Acad.Sci.ISSN007；ANNALSOFTHENEWYORKACADEM；Issue:EvolvingChallenges；LDL-cholesterolversusHDL；LinaBadimon1,2andGemmaVi；CardiovascularResearchCe；CIBEROBN-Pathophysiology；Ather
Ann.N.Y.Acad.Sci.ISSNANNALSOFTHENEWYORKACADEMYOFSCIENCESIssue:EvolvingChallengesinPromotingCardiovascularHealthLDL-cholesterolversusHDL-cholesterolintheatheroscleroticplaque:in?ammatoryresolutionversusthromboticchaosLinaBadimon1,2andGemmaVilahur1CardiovascularResearchCenter,CSIC-ICCC,HospitaldelaSantaCreuiSantPau,IIB-SantPauandCIBEROBN-PathophysiologyofObesityandNutrition,Barcelona,Spain.2CardiovascularResearchChair,UniversitatAut`onomadeBarcelona,Barcelona,SpainAddressforcorrespondence:LinaBadimon,CardiovascularResearchCenter,c/SantAntoniMaClaret167,08025,Barcelona,Spain.lbadimon@csic-iccc.org1Atherosclerosisisacomplexdiseaseinwhichmanyprocessescontributetolesiondevelopment.Yet,itiswellacceptedthathighserumlevelsoflow-densitylipoproteins(LDL)playamainroleintheinitiationandprogressionofatherosclerosis.DespitecurrentlyavailableoptimalLDL-loweringtherapies,aworrisomenumberofclinicaleventsstilloccur.Theprotectiveeffectofhigh-densitylipoproteins(HDL)inatherosclerosis,eitherbysuppressingvascular-LDLaccumulation,in?ammation,oxidation,endothelialdamage,andthrombosis,hassupportedtheneedoftheuseofHDL-raisingtherapiestoaddressthisresidualrisk.Resultsobtainedinsomestudies,however,haveshownthatHDLquality,ratherthanquantity,shouldbethetargetoffuturepharmacologicaltherapies.Here,wewill?rstexplorethemechanismbywhichexcessLDLisfundamentalinthedevelopmentofatherosclerosisanditsthromboticcomplications,behavingasafactorthatintroduceschaosinthevascularwall.Afterwards,wewillexplorehowfunctionalHDL,throughvariouscellularandmolecularmechanisms,facilitatestheresolutionofthisvascularchaosbysuppressionofatherosclerosisprogressionandinductionofregression.Keywords:high-low-atherothrombosisIntroductionCardiovascularriskfactorsAtheroscleroticvasculardisease,whichencom-passescoronaryheartdisease,cerebrovasculardis-ease,andperipheralarterialdisease,isresponsibleforthemajorityofcasesofcardiovasculardisease(CVD)inbothdevelopinganddevelopedcoun-tries.LargeprospectivecohortstudiessuchastheFraminghamHeartStudyandtheSevenCoun-triesStudy1,2havedemonstratedtheimportanceofmajorCVDriskfactorsintheappearanceofvascularevents(Fig.1).Screeningforandtreat-ingtheseconditionshasbecomethebasisofmanypublishedguidelinesofriskassessmentandreduc-tionstrategies.3Itisapparent,however,thatasub-stantialproportionofcardiovasculareventsoccurinindividualswhoexhibitnoneoftheseclassicriskfactors.4ThishasledtoanincreasinginterestinidentifyingnovelbiomarkersthatmightimprovetheglobalriskpredictionofCVD.Inrecentyears,anumberofemergingmarkershavebeenproposedassigni?cantpredictorsofatherosclerosisanditsthromboticcomplications(Fig.1).However,theINTERHEARTstudy5underscoredagaintheim-portanceofplasmalipoproteinsinthepathogenesisofCADandacuteMI.Assuch,theApoB:ApoA1ratio(anindexofatherogeniclipoproteinsandprotectivelipoproteins,respectively)appearedasastrong,newriskfactorforCVDthathighlightedtheimportanceofhigh-densitylipoproteincholes-terol(HDL)levelsasarisk-reducingfactor.BesidestheApoB:ApoA1ratio,homocysteine,?brino-gen,lipoprotein(a)[Lp(a)],low-densitylipopro-tein(LDL)ofsmalldenseparticlesizeandhigh-sensitivityC-reactiveprotein(hs-CRP)havedoi:10.1111/j.12.06480.x18c2012NewYorkAcademyofSciences.Ann.N.Y.Acad.Sci.C32??Badimon&VilahurLDLvs.HDLinatherothrombosisFigure1.Classicalandnovelcardiovascularriskfactors.gainedinterestinthelastyearstotheextentthatmostofthemareaccuratelymeasuredinroutineclinicalpracticeandspeci?ccut-offvalueshavebeenproposed.6,7LDLandatherosclerosisdevelopmentAtherosclerosis:intimalLDLasatriggeringfactorAtherosclerosisresultsfromacomplexinterplaybe-tweencirculatingfactorsandvariouscelltypesinthevesselwall,triggeredbythechronicandrepeatedexposuretopathogenicfactors,withhighlevelsofLDLbeingakeycontributorfortheinitiationandprogressionofatherosclerosisdevelopment.8C10EffectofLDLsonendothelialdysfunction.Inhealthyconditions,theendotheliumcontrolsthevasculartone,maintainsthebalancebetweenthrombosisand?brinolysis,andregulatesthere-cruitmentofin?ammatorycellsintothevascularwall.Theseeffectsarebroughtaboutbythereleaseofseveralmolecules,includingnitricoxide(NO),prostacyclin(PGI2),endothelium-derivedhyperpo-larizingfactor,andendotelin-1.NOplaysacentralatheroprotectiverolethroughtheregulationofvas-culartone,inhibitionofplateletaggregation,sup-pressionofvascularsmoothmusclecell(VSMC)proliferation,andblockadeofleukocyteadhesionandtransmigration.However,theexposuretohigh-LDLlevelshasshowntodecreaseNObioavailabilityeitherbyreducingtheconcentrationand/oractiva-tionofNOsynthetase(eNOS)orbyenhancingNOdegradation.11Endothelialdysfunction,character-izedbythereductionofNOavailability,isthepre-cedingsteptoLDLentrywithinthearterialintima.LDLisaheterogeneousclassoflipoproteinparticlesconsistingofahydrophobiccorecon-tainingtriglyceridesandcholesterolestersinahydrophilicshellofphospholipids,freecholesterol,andapolipoproteins,predominantlyB-100.Theen-tryandretentionofLDLinthesubendotheliallayermainlydependsonitssustainedplasmalevels.12However,otherpossibledeterminantslikelipopro-teinsize,cholesterolenrichment,endothelialper-meability,andendothelialcellCderivedbiosyntheticactivity(i.e.,synthesisofthebasementmembraneandextracellularmatrix,ECM)mayalsoaffectLDLentryandretention.1319c2012NewYorkAcademyofSciences.Ann.N.Y.Acad.Sci.C32??LDLvs.HDLinatherothrombosisBadimon&VilahurOnceintheintimalspace,proteoglycansarere-sponsiblefortrappingtheLDLparticlesinthear-terialintima.Chondroitinsulphateproteoglycans,suchasversican,arethemainstructuralproteo-glycansoftheECMandareconsideredimportantatherogenicelementsgiventhattheycanstronglyinteractwith,retain,andaggregatecholesterol-richlipoproteins.LDLparticlesarethosewiththegreatestcapacityforinteractingwiththeproteogly-cans.Thelengthandnumberofglycosaminogly-canchainsinproteoglycansproducedbyVSMCs,aswellastheirdegreeofsulfatation,alsodeter-minestheformationofinsolublecomplexesbe-tweenthesemoleculesandthecapacityforretentionoftheLDLparticlesinthearterialintima.OnceretainedbyECMcomponents,LDLparticlesun-dergomodi?cationprocessesbecauseoftheactionofcertainoxidants(lipoxygenase,myeloperoxidase,freeradicals,etc.)and/orbecauseofproteolytic(kinase,tryptase,metalloproteinases,thrombin,etc.),lipolytic(sphingomyelinase,phospholipaseA2,phospholipaseC,etc.),andhydrolyticenzymes(esterase).Thesechemicaland/orstructuralchangesgeneratedifferenttypesofmodi?edLDLparticles,ofwhichaggregatedLDL(agLDL)andoxidatedLDL(oxLDL)arethemosthighlyfound.Inourlaboratory,wehavedemonstratedthattheinterac-tionbetweenversican(ECMproteoglycan)andLDLproducesstructuralchangesintheLDLparticlethatleadtoagLDLinatheroscleroticlesions.14,15Twofamiliesoflipoproteinreceptorsareconsid-eredresponsibleforLDLuptakebycellsofthevascu-theLDLreceptorfamilyandthescavengerreceptorfamily.ldlreceptorfamily.The?rstmemberoftheLDLreceptorfamily,theLDLreceptor(LDL-R),isinvolvedinthecellularbindingandinternaliza-tionofplasmaLDL(native).OthermembersofthisfamilyaretheLRP1,LRP-1bandLRP-2/megalin,apolipoproteinEreceptor2(apoER2),MEGF7,verylow-densitylipoproteinreceptor(VLDL-R),LRP5,andLRP6.10AlthoughtheLDL-Rexclusivelymedi-atestheendocytosisofapoE-andapoB-containinglipoproteinparticles,LRP1bindsawidevarietyofligandsandisinvolvedinmultipleinternalizationprocesseslikeendocytosis,phagocytosis,andselec-tiveuptake.16TheLRP1lipoproteinligandsincludeapoE-enrichedVLDL,lipoproteinlipase,lipopro-teinlipase-triglycerideCrichlipoproteincomplexes,andLp(a).Inourgroup,wehaveidenti?edagLDLasanewligandforLRP1.17TherelevanceofLRP1asareceptorinvolvedonagLDLuptakeisenhancedbyfurtherdemonstrationthatLRP1bindsandmedi-atestheinternalizationofagLDLinhumancoronayandaorticVSMCs,andthatthiseffectisnotdown-regulatedbyexcesscholesterol,asitisthecasefortheLDLR.UnliketheLDL-R,whichonlyactsinlipidmetabolism,LRP1alsoparticipatesinsignaltransduction.IthasbeendescribedthatLRP1inter-actswiththeplatelet-derivedgrowthfactor(PDGF)receptorandthatthecontrolofPDGFsignalingbyLRP1protectsagainstatherosclerosis.18Inaddition,thecytoplasmicdomainofLRP1hasbeenshowntoserveasadockingsiteforcytoplasmicadaptorandscaffoldingproteinsinvolvedinsignaltrans-duction.16Thus,byitsdualroleasacargoreceptorandasignaltransductionreceptor,LRP1regulatescriticalcellularphysiologyandsignaltransductionevents.Inmacrophages,differentpathwaysforagLDLin-ternalizationhavebeendescribed,amongthembe-ingpinocytosis,phagocytosis,andpathocytosis.Inpathocytosis,agLDLbecomessequesteredinlargeamountswithinsurface-connectedcompartmentsofhumanmonocyteCderivedmacrophages.LDLuptakeintosurface-connectedcompartmentshasbeendescribedtotakeplacethroughandunidenti-?edreceptor.LRP1hasalsobeenassociatedwithmacrophages19,20andVSMCswithinthehu-manatheroscleroticlesions.21Yet,littleisknownaboutthefactorsthatregulateLRP1expressioninthesecellsduringatheroscleroticlesionprogres-sion.IthasbeendescribedthatLRP1mRNAlevelsareincreasedbycolony-stimulatingfactor-1andinsulin,whereastheyaredecreasedbytransforminggrowthfactor-?(TGF-?)andlipopolysaccharide.10Inourgroup,wedemonstratedthatagLDLstronglyupregulateLRP1expressionatthetranscriptionallevel,leadingtoalargeincreaseinLRP1proteinexpression.14Accordingly,wedetectedLRP1over-expressioninthevesselwallofhypercholesterolemicanimals.14Scavengerreceptorfamily.Thescavengerre-ceptorfamilyhasatleasteightdifferentsubclasses,22whichbearlittlesequencehomology.Scavengerre-ceptorsrecognizeawidevarietyofligandsincludingoxLDL,apoptoticcells,andpathogens.Althoughthepathophysiologicalrolesplayedbythesere-ceptorsinhumandiseasearestillunproven,data20c2012NewYorkAcademyofSciences.Ann.N.Y.Acad.Sci.C32??Badimon&VilahurLDLvs.HDLinatherothrombosisfrommurinemodelsofatherosclerosishavedemon-stratedasigni?cantroleinatheroscleroticfoamcelldevelopmentandvascularlesiondevelopmentfortworeceptors,thetypeAscavengerreceptor(SR-A)andthetypeBscavengerreceptor(CD36).SR-Aiso-formsarelargelyexpressedonmacrophagesbutcanalsobedetectedonendothelialandVSMCs.23SR-Aseemstohaveapivotalroleonfoamcellformation,sincemicesusceptibletodiet-inducedatherosclero-sisandlackingSR-Ashowedsigni?cantlyreducedatheroscleroticlesionsize.24Ontheotherhand,CD36isexpressedinmonocytes,macrophages,platelets,endothelium,adipocytes,andVSMCs.Al-thoughSR-Arecognizestheoxidizedapoproteinportionofthelipoproteinparticle,CD36recog-nizeslipidmoitiesofoxLDL.Interestingly,CD36bindswithhighaf?nitytoanovelclassofoxidizedphosphatidylcholinefoundinoxLDL.10Finally,theLOX-1isatypeEscavengerrecep-tor,expressedbyendothelialcells,macrophages,andVSMCs,whichalsorecognizesoxLDL.LOX-1isatypeIIglycoproteinconsistingofashortintracellu-lardomain,atransmembrane-spanningregion,andanextracellularC-typelectindomain.InadditiontoactingasamembranereceptorforoxLDL,solu-bleformsofLOX-1havebeenfoundtobesecretedbyTNF?-stimulatedendothelialcells.25LDLandinnateimmunityresponseinatheroscle-rosisprogression.Anotherimportantfeaturedur-ingthedevelopmentofatheroscleroticlesionsistheendothelialtransmigrationofcirculatingmono-cytesintotheintravascularspace.LDLparticles,es-peciallythemodi?edforms,increasetheexpressionandsecretionofsolublechemotacticcompounds(MCP-1,IL8)andenhancetheexpressionofad-hesionmoleculessuchasintegrinsandselectins,whichareexposedonthesurfaceofactivateden-dothelialcellsandfavorleukocyte(monocyteandTcell)recruitment,adhesion,andtransmigration.9Inadditiontotheeffectsonthevascularendothe-lium,modi?edLDLparticlesdirectlyfavortheentryofmonocytesinthevascularwallthroughapro-cessthatisthoughttobemediatedbyCD11andtheproteinkinaseC(PKC)pathway.Theentryofmonocytestakesplacethroughthespaces(junc-tions)betweenendothelialcells,preferablyinar-easwherethebasallaminaisenrichedwithmod-i?edLDLparticles.Then,in?ltratedmonocytesdifferentiateintomacrophagesandexpressscav-engerreceptorssuchasCD36andLOX-1,whichinternalizemanyofthecholesterolmoleculesandcholesterolesterscontainedinmodi?edLDLparti-cles.Cholesterolinternalizationleadstotheforma-tionoffoamcells,acharacteristiccellconstituentofatheroscleroticlesions.Inturn,foamcellsse-creteproin?ammatorycytokines,growthfactors,tissuefactor(TF),interferon-?,metalloproteinases(MMP),andreactiveoxygenspeciesthatmaintainthechemotacticstimulusforleukocytesadheredtothevascularendothelium,increasetheexpres-sionofscavengerreceptors,enhancemacrophagereplication,andregulateVSMCaccumulationintheintima.LDLsandSMC:plaquevulnerability.VSMCsarethemajorcomponentofthevascularwallthat,un-dertheeffectofatherogenicstimuli,undergophe-notypicchangesrangingfromdifferentiationtotheacquisitionofasyntheticphenotype.Thus,VSMCswithanonproliferativecontractilephenotype,typ-icalinthevascularmediaofhealthyarteries,trans-formintoactivelyproliferativecellsandmigratetowardthevascularintima,attractedbytheabove-mentionedchemotacticagents.26There,VSMCsex-pressavarietyofreceptorsforcholesteroluptake,mainlyLRP1,therebyparticipatingintheearlyac-cumulationoflipidswithintheplaque.AlthoughVSMCsaccountfor90C95%ofthecellcomponentininitiallesions,thisproportiondecreasesto50%inadvancedatheroscleroticlesions,makingthoseplaquesmorevulnerableforrupture.Indeed,un-stableplaquescontainasubstantiallipidcore,littlecollagen,andasmallnumberofVSMCs.Thesedatare?ecttheimportanceofidentifyingandelucidatingthecellmechanismsthatleadtoVSMClossinad-vancedlesions.Ontopofthis,atherogenicconcen-trationsofLDLsigni?cantlyreducethemigratorycapacityofhumanVSMCs,therebycontributingtothevulnerabilityoftheseadvanced-stagedplaques.Inthisregard,wehaverecentlyshown,byproteomicapproachesandconfocalmicroscopy,thatLDLpar-ticlesaffecttheexpressionandphenotypicpro?leofdifferentcytoskeleton-relatedproteins,includingthemyosinlightchaininboththeessentialandreg-ulatoryisoforms.27AtherogenicconcentrationsofLDLsinducemyosinregulatorylightchainphos-phorylation,akeyeventintheformationofactinCmyosincomplexesduringcellmigrationandthedynamicsofactin?berformation.27Thisprocessc2012NewYorkAcademyofSciences.Ann.N.Y.Acad.Sci.C32??21LDLvs.HDLinatherothrombosisBadimon&VilahurishighlyregulatedbyproteinssuchasgelsolinandHSP27.28ImpactofLDLonatherothrombosisBecauseoftheproximityofTFandlipid-richareasinadvancedatheroscleroticlesions,alinkbetweenLDLparticles,TFexpression,andthromboticriskhasbeenestablished.Indeed,studiesoftherela-tivethrombogenicityofthevariouscomponentsofatheroscleroticplaqueshavedemonstratedthatthelipid-richnucleusisuptosixtimesmorethrom-bogenicthanallothercomponents.29Inaddition,wehavealsoshownthatinhibitionofTFbylocaladministrationofTFpathwayinhibitor(TFPI)ef-fectivelyreducesarterialthrombosisinatheroscle-roticlesions.30TFfoundinsuchalipid-richcoremightlargelyderivefrommacrophagesandVSMC-derivedfoamcells.Indeed,LDL-ladenfoamcellshaveshowntoreleaseTF,increasingplaquesuscep-tibilitytothrombusformation.Ontheotherhand,wehavereportedthattheinteractionbetweenLRP-1andLDLaggregatesisoneofthemechanismsthatinduceVSMCTFexpressioninaprocessthatdependsonRhoAtranslocationtothemembraneandthereleaseofmicroparticlesenrichedinactiveTFtotheECM.31,32Accordingtoourobservations,VSMCsmightcontributetoincreasingnotonlythethrombogencityoftheatheroscleroticplaquebutalsothecirculatingTF-enrichedmicroparticles.LDLlevelsandtheincidenceofCVDTakinginmindthemultipledeleteriouseffectsas-sociatedwithhigh-LDLcholesterollevels,lipid-loweringstrategieshavebecomethecornerstoneforthepreventionandtreatmentofCVD.Indeed,thepublicationofthelandmark4Sstudyshowedatotalmortalityreductionof29%inischemicpa-tientstreatedwithsimvastatin.Sincethen,numer-ousstudieshavecon?rmedthatstatinsreducecar-diovascularriskby20C30%.33C35Infact,arecentmeta-analysis(14trialswithstatins,90,056patients,meanfollow-upof?veyears)concludedthatforevery40mg/dLdecreaseinLDLcholesterol,car-diovasculareventsarediminishedby21%.TheseobservationssuggestthepossibilitythatamoreintenseLDL-cholesterolreductioncouldinducehigherpro?ts.Infact,thishypothesiswascon?rmedinseveralstudiesusinghigherdosesormorepo-tentstatins,suchasIDEAL,36TNT,37andPROVE-IT.34Moreover,theASTEROIDstudy38raisedthepossibilitythatreducingLDLtoanaverageof60mg/dLwasassociatedwithasigni?cantregressionofatherosclerosisassessedbyIVUSafter24monthsoftreatment.Recently,theSATURNtrialhasshownthatmaximaldosesofrosuvastatinandatorvas-tatinresultedinsigni?cantregressionofcoronaryatherosclerosis.39Regardlessofintensivetreatmentwithstatins,theresidualriskofhavinganothercardiovasculareventremainsveryhigh.Forinstance,despiteachievingLDL-Cof62mg/dLinPROVE-IT,34theresidualriskofdeathandischemiccardiovasculareventsinpatientsremainedupto22.4%aftertwoyearsoffollow-up.Inotherwords,alternativestrategiesareclearlyrequiredtobridgethe～75%gapleftafterstatintreatmentinpreventionofmajorcar-diovascularevents.Effortsare,therefore,currentlyfocusedonreducingtheresidualriskthroughad-ditionalstrategiesdifferentandcomplementarytostatins,suchasincreasedHDLcholesterol.ImpactofHDLinatherothrombosisClinicalimpactofHDLMultipleepidemiologicalstudieshaveprovidedro-bustevidenceofaninversecorrelationbetweenHDLplasmalevelsandcardiovascularrisk.40TheFraminghamstudy?rstcon?rmedthatlowHDL-cholesterolconcentrationpredictedfuturecardio-vascularevents,andwas,alongwiththetotalcholesterol/HDL,theonlyindependentpredictorofCVD.Morerecentstudies(PROCAM,41Goldbourtetal.42)con?rmedthisrelationship,andfoundthatpatientswithHDL&35mg/dLhadanincidenceofcardiovasculareventseighttimeshigherthanindividualswithHDL&65mg/dL.Moreover,ameta-analysis,43includingfourpopulationstudies(FHS,44LRCF,45CPPT,46andMRFIT47),showedthatforeveryincreaseofHDL-cholesterolof1mg/dL,therewasa1.9to2.3%reductionincardio-vascularriskinmenand3.2%inwomen.Thisrela-tionshipholdsevenforlow-LDLcholesterollevels.Infact,aposthocTNTclinicaltrial,includingpa-tientswithLDLvaluesbelow70mg/dL,foundthatthosewithinthehighestquintileofHDL-cholesterolhadalowerriskofcardiovasculareventsthanthoseinthelowestquintile.TheimportanceofHDLwasalsohighlightedinasubanalysisoftheMIRACLtrial,48whichshowedthatlowHDLpredictstheriskofrecurrentcar-diovasculareventsintheshortterm(fourmonths)afteranACS,whilehighLDL-Cvaluesdonot22c2012NewYorkAcademyofSciences.Ann.N.Y.Acad.Sci.C32??包含各类专业文献、中学教育、生活休闲娱乐、高等教育、应用写作文书、各类资格考试、19LDL-cholesterol versus HDL-cholesterol in the atherosclerotic plaque inflammatory resolution versus等内容。