(8.1)-10.心血管系统疾病高级病理学

(GeneralMolecularPrinciplesofCardiovascularDisease•Uniquepropertiesandbiomarkers•Microenvironmentsandautocrineandparacrinere•embryo-specificgenetheliumisacontinuoussheetofcellslininrtreethatformathromboresistantselectivepregulatesmanyaspectsofbloodandbloodvesselfunction内皮细胞的生理功能和病理状态下功能不全的表现EndothelialdysfunctionExposureofECstohighlevelsofstimuliforVascularSmoothMuscleCells(SMCs)•Maintainvasculartone•FactorsthatmaintainSMCsinaquiescentstateincludeheparansulfate,NO,andtransforminggrowthfactor-α(TGF-α).VascularSmoothMuscleCells(SMCs)expressionwhileexpresfoamcellsthroughingestionoflipidscytokinesproducedbyplatVascularSmoothMuscleCells(SMCs)•Importantregulatorsofvascularremodelingwithsecretionofmatrixmetalloproteinases(MMPs),MT1-MMP,t•Undergotransdifferexpressionwhileexpresfoamcellsthroughingestionoflipids•UndergotransformationtoSMCplasticityisanimportantfeatureintheresponseofthevascularwalltovasAtherosclerosis(AS)ASisachronicvasculardiseaseinitiallydevelopingintheintimaofelasticandlargermusculararteriesandcharacterizedbythepresenceoffibro-inflammatorylipidplaques(atheromas)thatimpingeonthevascularlumenandcanrupturetocausesuddenocclusion.;•Familyhistory(e.g.,familialhypercholester•Multiplegenes(polygenic),interactwiththeenvircoronaryarterydiseaseswi•ExtensiveDNAhypomethylationhasbeenassociatedwithestablishedriskfactors—hyperlipidemia,hyperECG,electrocardiogram;HDL-C,high-densitylipoproteifromobservationalstudies,JHypertension16[Suppl6]:3,1998.)PathogenesisofAS?ThebasicstructureofanatheromatousplaqueprincipalcomponentsofatheromaKeypathogeniceventsofAS•Accumulationoflipids(Ox-LDLdThreestagesofASStageI:PlaqueInitiationandemigrationStageII:AdaptionStageEndothelialinjuryEarlyhumanatheroscleroticlesionsbeginatsitesofintact,butHemodynamicDisturbancesandAS•predilectionsiteofAS–shearstressesarelowbutfluceg.branchpointsandalongtheposteriorwalloftheabdominalaorta•HypertensionenhancestheseverityofAS-disruptsnormalrepairofECs•Hemodynamicforcesinducegeneexpressionofpro-ASmolecules:•Nonturbulentlaminarflowleadstotheinductionof“atheroprotective”genesinECsHypercholesterolemiaandASHypercholesterolemiaisamajorcholesterolesters.•Hyperlipoproteinemiaareassociated•Homozygousfamilialhypercholesterolemia,causedbydefectivreceptorsandinadeinfarctionby20yearsofage•EpidemiologicanalysesdthelevelsoftotalplasmacholesterolorLDLandtheseverityofAS•LoweringserumcholesprogressionofAS,causesregressionofsomeplaques,andreducestheriskforcardiovascularevents.ThemechanismsbywhichdyslipiIntimallipoprotein(LDL)ac•impairedECfunctionbychronichypercholesteAchangeinthetypeofconnectivetissueandproteogd•viatheactionofoxygenfreeradicalsgeneratedbymacrophagesor•Ox-LDLstimulatesthelocalreleaschemokines,increasingmonoLDLplaysaprominentcausalroleinASThemechanismsbywhichdyslipi•Macrophagesbecomefoamtoproducepro-inflammatorymediators.----oxidizedLDLandcholesterolcrystals.•TGF-B--regulatessecretionofcollagen,matrixproteinsanddifferentiationofSMCsundergophenotypicswitchingfromcontractilequiescentcellstosecretorySMCsthatproliferateandmigrateSMCProliferationandMatrixSynthesisamatureatheromaandstabilizesatheroscleroticplaapoptosisandbreakdownofmatrix,leadingtothedevelopmentofPlateletadhesionandactivationPlateletsareadherentontheprothromboticdamagedintimalsurfaceandbecomeactivatedandreleasemoleculesincluding•TGFB:organizationofthethrombusandincorporationintotheplaque•Thrombin,ADPandthromboxanePlateletisinvolveinthrombusdevelopment,SMCproliferation,EMCremodelanplateletactivationAtheroscleroticplaqueruptureAcutecoronarythrombosissuperimposedonanatheroscleroticplaquewithfocaldisruptionofthefibrouscap(arrow),triggeringfatalmyocardialinfarction.InflammationandAS•DysfunctionalECsexpressadhesionmoleculesthainfluenceoflocallyproducedchemokines.•MonocytesdifferentiateintomacrophagesandavidlyeproducetoxicoxygenspeciesgrowthfactorsthatstimulateSMCproliferation.•CholesterolcrystalsappeartobeparticularlyimportantinstigatorsofinflammationthroughactivationoftheinflammasomeandsubsequentInflammationandAS•Tlymphocytesrecruitedtotheintimainteractwiththemacrophagesgrowingintimallesionselaborateinflamwhichstimulatemacrophages,•AsaconsequenceofthechrleukocytesandvascularwallceSMCproliferationandmatrixsynthInflammationcontributestotheinitiation,progression,andcomplicationsofASDevelopmentofthenecroticcore•Thedeeperpartsofthethickenedintimaarepoorlynourished•Celldeathispromotedbyproteolyticenzymesreleasedbymacroph•Ox-LDLandotherreaNeovascularizationtranscriptionalactivationof•ThepresenceofpermanencytotheppreventssignificantreHigh-powerviewofthejunctionofthefibrouscapandcore,showingscatteredinflammatorycelNeovascularization•AngiogenesisisfrequentinadvancedAS•Itisprobablyamarkerofongoingdiseaseactivityandmaythuscharacterizehigh-riskplaques•Thenewmicrovesselsarefragile,areleaky,andexpresscellularadhesionmoleculesVCAM-1,resultinginlocalextravasationofplasmaproteins,erythrocytesandinflammatorycells.Thus,angiogenesisandinflammationoftencoexistandcouldmediaterapidplaqueprogressionFalkEetal.PathogenesisofAtherosclerosis.JAmCollCardiol2006ThecurrentlyheldviewofpathogenesisofASisembodiedintheresponse-to-injuryhypothesis.Thismodelviewsatherosclerosisasachronicinflamma