脂代謝紊亂與動(dòng)脈粥樣硬化課件

Cardiovasculardiseaseistheleadingcause

ofdeathamongadultsworldwide(1996)Coronarydisease 7.2millionCancer 6.3Cerebrovasculardisease 4.6Acutelowerrespiratorytractinfections 3.9Tuberculosis 3.0COPD(chronicobstructivepulmonarydisease) 2.9Diarrhea(includingdysentery) 2.5Malaria 2.1AIDS 1.5HepatitisB 1.2Cardiovasculardiseaseisthe1Coronarymortality:

alarmingworldwideforecastsCoronarymortality:

alarmingw2Atherosclerosis:

amultifactorialdiseaseAtherosclerosis:

amultifactor3MainriskfactorsforcoronaryheartdiseaseMainriskfactorsforcoronary4Globalprojectionsforthediabetesepidemic:

1995-2010Globalprojectionsforthedia5AtherosclerosisAtherosclerosis6Arterialwall:

structureandfunctionArterialwall:

structureandf7Differentstagesofatheroscleroticplaque

developmentDifferentstagesofatheroscle8Vascularendotheliummodification

inatherosclerosisVascularendotheliummodificat9Plaqueformation

1—Fattystreak

Plaqueformation

1—Fattystr10Plaqueformation

2—Fibrouscap

Plaqueformation

2—Fibrousc11Plaqueformation

3—Lipidcore

Plaqueformation

3—Lipidcor12Fromplaquetothrombosis,keyevent:

plaqueruptureFromplaquetothrombosis,key13Lipidcoreconstitution

ActivatedmacrophagesaccumulatelipidsLipidcoreconstitution

Activa14Lipidcoreconstitution

LDLoxidationLipidcoreconstitution

LDLox15Parietalvascularinflammation

TheactivatedmacrophageproducesinflammatorycytokinesParietalvascularinflammation16

Parietalvascularinflammation

NFkBactionintheinflammationprocess

Parietalvascularinflammatio17DiabetesandatherosclerosisDiabetesandatherosclerosis18TobaccoandatherosclerosisTobaccoandatherosclerosis19DyslipidemiaandatherosclerosisDyslipidemiaandatheroscleros20HTN,hemodynamicfactorandatheroclerosisHTN,hemodynamicfactorandat21Howtoreduceplaqueformation

InterventiononriskfactorsHowtoreduceplaqueformation22HowtoreducetheriskofplaqueruptureHowtoreducetheriskofplaq23HowtoreducetheriskofthrombosisHowtoreducetheriskofthro24~10%Weightloss=~30%Visceral

adiposetissueloss~10%Weightloss=~30%Viscer25CharacteristicsofanunstableplaqueCharacteristicsofanunstable26Plaquevulnerabilityfactors

IntrinsicfactorsPlaquevulnerabilityfactors

27ModificationofextrinsicvulnerabilityfactorsModificationofextrinsicvuln28

Plaquerupture

Themainreleasingfactors

Plaquerupture

Themainrele29ClassificationoflipidsandlipoproteinsClassificationoflipidsandl30CharacteristicsoflipoproteinsCharacteristicsoflipoprotein31Triglyceride-richlipoproteins:

size,structureandcompositionTriglyceride-richlipoproteins32DigestionandmetabolismofdietaryfatDigestionandmetabolismofdi33HDLmetabolismandreversecholesteroltransportHDLmetabolismandreversecho34Cholesteroleffluxandreversecholesterol

transportismodulatedbytworeceptorsCholesteroleffluxandreverse35AtherogenicityofsmalldenseLDLAtherogenicityofsmalldense36Sizeandapolipoproteincompositionarethemainfactorsdeterminingatherogenicityoftriglyceride-richparticlesSizeandapolipoproteincompos37Sizeandapolipoproteincompositionarethemainfactorsdeterminingatherogenicityoftriglyceride-richparticlesSizeandapolipoproteincompos38ApoC-IIImodulatesVLDLApoC-IIImodulatesVLDL39ApoC-IIIinapoBparticlesisatherogenicApoC-IIIinapoBparticlesi40RelationshipbetweenapoC-IIIinapoB

containinglipoproteinsandatherogenicityRelationshipbetweenapoC-III41PROCAMStudy

MI-IncidenceaccordingtoLDL-cholesterolandtriglyceridesPROCAMStudy

MI-Incidenceacco42PROCAMStudy

CHDriskaccordingtoLDL-CandTG

increasedTGconfersraisedCHDriskatalllevelsofLDL-CPROCAMStudy

CHDriskaccordin43HDL:

ananti-atherogeniclipoproteinHDL:

ananti-atherogeniclipop44HDLmetabolism:

5keygenes

HDLmetabolism:

5keygenes45HDL:

apoAI-richparticlesHDL:

apoAI-richparticles46ApoA-IprotectsagainstatherosclerosisApoA-Iprotectsagainstather47ApoA-IIprotectsagainstatherosclerosis

ThehumanapoA-IItransgenicmousemodelApoA-IIprotectsagainstathe48Genesandenvironmentintype2diabetes

andatherosclerosisGenesandenvironmentintype49PimaIndians

ThriftygenesPimaIndians

Thriftygenes50AboriginalCanadiansOji-CreeAboriginalCanadiansOji-Cree51Obesity,type2diabetes,atherosclerosisObesity,type2diabetes,athe52TheMetabolicSyndromeTheMetabolicSyndrome53Visceralobesityisassociatedwithacluster

ofmetabolicabnormalitiesVisceralobesityisassociated54TheatherogenictriadTheatherogenictriad55PROCAMStudy:

MI-IncidenceaccordingtoLDL-cholesterolandtriglyceridesPROCAMStudy:

MI-Incidenceacc5670%ofmenwithCHDhadalowHDL≤44mg/dL

FraminghamMaleOffspring35-5470%ofmenwithCHDhadalow57Obesity,type2diabetes,lipidmetabolism

ThekeyroleofthetranscriptionalfactorsPPARsObesity,type2diabetes,lipi58

PPARadiscoveryelucidates

mechanismofactionoffibrates

PPARadiscoveryelucidates

me59ThedifferentPPARsubtypesThedifferentPPARsubtypes60PPARa:

atranscriptionfactorPPARa:

atranscriptionfactor61PPARa:

transcriptionalactivationintwostagesPPARa:

transcriptionalactivat62PPARa:

transcriptionalactivationintwostages

PPARa:

transcriptionalactivat63TranscriptionalactivationbyPPARaTranscriptionalactivationby64

PPARs:

regulationoflipoproteinmetabolismbyPPARa

PPARs:

regulationoflipoprot65PPARaactivatorslowersmalldenseLDLPPARaactivatorslowersmalld66AnapolipoproteinidentifiedAnapolipoproteinidentified67Plasmatriglycerideandcholesterollevels

forhumanapoA-VtransgenicmicePlasmatriglycerideandcholes68Plasmatriglycerideandcholesterollevels

forapoA-VknockoutmicePlasmatriglycerideandcholes69AllelefrequenciesforSNP3according

toplasmatriglyceridelevelsAllelefrequenciesforSNP3a70PPARaactivatorsinduceapoA-V

geneexpressionPPARaactivatorsinduceapoA-71PPARaactivateshumanapoA-V

transcriptionthroughtwoPPREsPPARaactivateshumanapoA-V

72

PPARa:apoA-l,apoA-ll,LPL,

ABCA-1andSR-BIexpression

PPARa:apoA-l,apoA-ll,LPL73PPARaactivatorsinduceABCA-1geneexpression

inhumanmacrophagesPPARaactivatorsinduceABCA-174PPARaactivatorsinducecholesterolefflux

fromhumanmacrophagesPPARaactivatorsinducecholes75CLA-1/SR-BIproteinmaypromotecholesterol

removalfromperipheralcellsCLA-1/SR-BIproteinmaypromot76CLA-1expressionisregulatedbyPPARaactivators

indifferentiatedhumanmacrophagesCLA-1expressionisregulated77PPARaactivatorsinducecholesterolefflux

andreversecholesteroltransportPPARaactivatorsinducecholes78PPARsinthevascularwallPPARsinthevascularwall79MechanismsoftransrepressionbyPPARaMechanismsoftransrepression80ThetranscriptionfactorNFkB:

akeyroleintheinflammatoryresponseThetranscriptionfactorNFkB:81ModelofNFkBsignalpathwayinhibition

byPPARaactivatorsModelofNFkBsignalpathwayi82PPARaactivatedbyfibratesinhibitsIL-1b

inducedexpressionofCOX-2inSMCPPARaactivatedbyfibratesin83

FenofibratereducesplasmaIL-6

inpatientswithCAD

FenofibratereducesplasmaIL84

FenofibratelowersplasmaCRP

inpatientswithCAD

FenofibratelowersplasmaCRP85PPARaactivatorsreduceadhesionmolecule

productionbyinterferingwithNFkBPPARaactivatorsreduceadhesi86PPARactivatorsreduceendothelin-1production

byinterferingwithAP-1transcriptionfactorPPARactivatorsreduceendothe87PPARaactivatorsinhibitthrombininducedET-1secretioninhumanmacro-andmicrovascularendothelialcellsPPARaactivatorsinhibitthrom88PPARaactivatorsreducetissuefactorproductionby

interferingwithNFkBandAP-1transcriptionfactorsPPARaactivatorsreducetissue89PPARaactivatedbyfibratesnegatively

regulatesfibrinogen-bexpressionPPARaactivatedbyfibratesne90Statins

Molecularmechanismsofaction

SREBPfeedbackcontrol

Statins

Molecularmechanismso91SREBP*regulatestheLDLreceptor

Three-stepactivationprocessSREBP*regulatestheLDLrecep92CommonpropertiesofPPARaactivators

andstatins

Parietalvasculareffects

CommonpropertiesofPPARaact93StatinsandPPARaactivators,similareffects

Similareffector,PPARa?

StatinsandPPARaactivators,94StatinsinducePPARaactivityStatinsinducePPARaactivity95HumanapoA-ImRNAisinduced

bystatinsinadose-dependentmannerHumanapoA-ImRNAisinduced

96StatinsactonapoA-ImRNA

expressionatthetranscriptionallevel

InhibitionbyactinomycinD

StatinsactonapoA-ImRNA

e97StatineffectonapoA-Isynthesis

isrelatedtoitsmodeofaction

Inhibitionbymevalonate

StatineffectonapoA-Isynth98StatinsandPPARaactivators

increasehumanapoA-IgeneexpressionStatinsandPPARaactivators

i99Simvastaticacidreducesinduced

LPSMMP9secretionSimvastaticacidreducesinduc100Parietalvasculareffectsofstatins(1)

EndothelialcellsParietalvasculareffectsofs101Parietalvasculareffectsofstatins(2)

Monocytes,macrophagesParietalvasculareffectsofs102PPARaactivatorsactonthemainfactors

involvedintheonsetofatherosclerosisPPARaactivatorsactonthema103

VA-HIT

VA-HIT104VA-HITcontVA-HITcont105

DAIS

DAIS106

DAIScont

DAIScont107

HHS

HHS108HHScontHHScont109

4S

4S110

4Scont

4Scont111

CARE

CARE112

CAREcont

CAREcont113

WOSCOPS

WOSCOPS114

WOSCOPScont

WOSCOPScont115

LIPID

LIPID116

LIPIDcont

LIPIDcont117

AFCAPS/TexCAPS

AFCAPS/TexCAPS118

AFCAPS/TexCAPScont

AFCAPS/TexCAPScont119

AVERT

AVERT120

AVERTcont

AVERTcont121

HPS

HPS122

HPScont

HPScont123

NCEPguidelines

NCEPguidelines124

NCEPguidelinescont

NCEPguidelinescont125

NCEPguidelinescont

NCEPguidelinescont126

NCEPguidelinescont

NCEPguidelinescont127

AHA/ACCguidelines

AHA/ACCguidelines128

ADAguidelines

ADAguidelines129

ADAguidelinescont

ADAguidelinescont130

LipidmanagementforprimarypreventionofCHD

inadults–ILIBrecommendations

Lipidmanagementforprimary131

LipidmanagementforsecondarypreventionofCHD

inadults–ILIBrecommendations

Lipidmanagementforsecondar132

LipidmanagementforsecondarypreventionofCHD

inadultswithdiabetesmellitus–ILIBrecommendations

Lipidmanagementforsecondar133

AbbreviationslistAS AtherosclerosisBL BaselineBMI BodyMassIndexBP BloodPressureCABG CoronaryArteryBypassGraftCAD CoronaryArteryDiseaseCARE CholesterolandRecurrentEventsCE CholesterolEsterCERP CholesterolEffluxRegulatoryProteinCETP CholesterolEsterTransferProteinCHD CoronaryHeartDiseaseCHF CongestiveHeartFailureChol Cholesterol COX-2 Cyclo-oxygenase-2CRP CReactiveProteinCV CardiovascularCVD CardiovascularDiseaseDM DiabetesMellitusECTIM StudyEtudeCasTemoinsdeIífarctusduMyocardeER EndoplasmicReticulumET-1 Endothelin-1GE GlycerolEstersHDL-C High-DensityLipoproteinCholesterolHL HepaticLipaseHT HypertensionICAM IntercellularAdhesionMoleculeIL InterleukinLCAT LecithinCholesterolAcetylTransferaseLDL-C Low-DensityLipoproteinCholesterolLPL LipoproteinLipasemg/d MilligramsperDaymg/dL MilligramsperDeciliterMI MyocardialInfarctionNFkB NuclearFactorBNS NotSignificantPAI-1 PlasminogenActivatorInhibitorType1 Plc PlaceboPPARs PeroxisomeProliferator-ActivatedReceptorsPROCAM ProspectiveCardiovascularMunsterStudyPPRE ResponsiveElementPTCA PercutaneousTransluminalCoronaryAngiographyRXR RetinoidXReceptorSig SignificantSREBP SterolRegulatoryElementBindingProteinTC TotalCholesterolTF TissueFactorTG TriglycerideTNF TumorNecrosisFactorUAP UnstableAnginaPectorisVCAM VascularCellAdhesionMoleculevs VersusWHR WaistHipRatio

AbbreviationslistAS Atheros134

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ReferencelistcontFigures55136Cardiovasculardiseaseistheleadingcause

ofdeathamongadultsworldwide(1996)Coronarydisease 7.2millionCancer 6.3Cerebrovasculardisease 4.6Acutelowerrespiratorytractinfections 3.9Tuberculosis 3.0COPD(chronicobstructivepulmonarydisease) 2.9Diarrhea(includingdysentery) 2.5Malaria 2.1AIDS 1.5HepatitisB 1.2Cardiovasculardiseaseisthe137Coronarymortality:

alarmingworldwideforecastsCoronarymortality:

alarmingw138Atherosclerosis:

amultifactorialdiseaseAtherosclerosis:

amultifactor139MainriskfactorsforcoronaryheartdiseaseMainriskfactorsforcoronary140Globalprojectionsforthediabetesepidemic:

1995-2010Globalprojectionsforthedia141AtherosclerosisAtherosclerosis142Arterialwall:

structureandfunctionArterialwall:

structureandf143Differentstagesofatheroscleroticplaque

developmentDifferentstagesofatheroscle144Vascularendotheliummodification

inatherosclerosisVascularendotheliummodificat145Plaqueformation

1—Fattystreak

Plaqueformation

1—Fattystr146Plaqueformation

2—Fibrouscap

Plaqueformation

2—Fibrousc147Plaqueformation

3—Lipidcore

Plaqueformation

3—Lipidcor148Fromplaquetothrombosis,keyevent:

plaqueruptureFromplaquetothrombosis,key149Lipidcoreconstitution

ActivatedmacrophagesaccumulatelipidsLipidcoreconstitution

Activa150Lipidcoreconstitution

LDLoxidationLipidcoreconstitution

LDLox151Parietalvascularinflammation

TheactivatedmacrophageproducesinflammatorycytokinesParietalvascularinflammation152

Parietalvascularinflammation

NFkBactionintheinflammationprocess

Parietalvascularinflammatio153DiabetesandatherosclerosisDiabetesandatherosclerosis154TobaccoandatherosclerosisTobaccoandatherosclerosis155DyslipidemiaandatherosclerosisDyslipidemiaandatheroscleros156HTN,hemodynamicfactorandatheroclerosisHTN,hemodynamicfactorandat157Howtoreduceplaqueformation

InterventiononriskfactorsHowtoreduceplaqueformation158HowtoreducetheriskofplaqueruptureHowtoreducetheriskofplaq159HowtoreducetheriskofthrombosisHowtoreducetheriskofthro160~10%Weightloss=~30%Visceral

adiposetissueloss~10%Weightloss=~30%Viscer161CharacteristicsofanunstableplaqueCharacteristicsofanunstable162Plaquevulnerabilityfactors

IntrinsicfactorsPlaquevulnerabilityfactors

163ModificationofextrinsicvulnerabilityfactorsModificationofextrinsicvuln164

Plaquerupture

Themainreleasingfactors

Plaquerupture

Themainrele165ClassificationoflipidsandlipoproteinsClassificationoflipidsandl166CharacteristicsoflipoproteinsCharacteristicsoflipoprotein167Triglyceride-richlipoproteins:

size,structureandcompositionTriglyceride-richlipoproteins168DigestionandmetabolismofdietaryfatDigestionandmetabolismofdi169HDLmetabolismandreversecholesteroltransportHDLmetabolismandreversecho170Cholesteroleffluxandreversecholesterol

transportismodulatedbytworeceptorsCholesteroleffluxandreverse171AtherogenicityofsmalldenseLDLAtherogenicityofsmalldense172Sizeandapolipoproteincompositionarethemainfactorsdeterminingatherogenicityoftriglyceride-richparticlesSizeandapolipoproteincompos173Sizeandapolipoproteincompositionarethemainfactorsdeterminingatherogenicityoftriglyceride-richparticlesSizeandapolipoproteincompos174ApoC-IIImodulatesVLDLApoC-IIImodulatesVLDL175ApoC-IIIinapoBparticlesisatherogenicApoC-IIIinapoBparticlesi176RelationshipbetweenapoC-IIIinapoB

containinglipoproteinsandatherogenicityRelationshipbetweenapoC-III177PROCAMStudy

MI-IncidenceaccordingtoLDL-cholesterolandtriglyceridesPROCAMStudy

MI-Incidenceacco178PROCAMStudy

CHDriskaccordingtoLDL-CandTG

increasedTGconfersraisedCHDriskatalllevelsofLDL-CPROCAMStudy

CHDriskaccordin179HDL:

ananti-atherogeniclipoproteinHDL:

ananti-atherogeniclipop180HDLmetabolism:

5keygenes

HDLmetabolism:

5keygenes181HDL:

apoAI-richparticlesHDL:

apoAI-richparticles182ApoA-IprotectsagainstatherosclerosisApoA-Iprotectsagainstather183ApoA-IIprotectsagainstatherosclerosis

ThehumanapoA-IItransgenicmousemodelApoA-IIprotectsagainstathe184Genesandenvironmentintype2diabetes

andatherosclerosisGenesandenvironmentintype185PimaIndians

ThriftygenesPimaIndians

Thriftygenes186AboriginalCanadiansOji-CreeAboriginalCanadiansOji-Cree187Obesity,type2diabetes,atherosclerosisObesity,type2diabetes,athe188TheMetabolicSyndromeTheMetabolicSyndrome189Visceralobesityisassociatedwithacluster

ofmetabolicabnormalitiesVisceralobesityisassociated190TheatherogenictriadTheatherogenictriad191PROCAMStudy:

MI-IncidenceaccordingtoLDL-cholesterolandtriglyceridesPROCAMStudy:

MI-Incidenceacc19270%ofmenwithCHDhadalowHDL≤44mg/dL

FraminghamMaleOffspring35-5470%ofmenwithCHDhadalow193Obesity,type2diabetes,lipidmetabolism

ThekeyroleofthetranscriptionalfactorsPPARsObesity,type2diabetes,lipi194

PPARadiscoveryelucidates

mechanismofactionoffibrates

PPARadiscoveryelucidates

me195ThedifferentPPARsubtypesThedifferentPPARsubtypes196PPARa:

atranscriptionfactorPPARa:

atranscriptionfactor197PPARa:

transcriptionalactivationintwostagesPPARa:

transcriptionalactivat198PPARa:

transcriptionalactivationintwostages

PPARa:

transcriptionalactivat199TranscriptionalactivationbyPPARaTranscriptionalactivationby200

PPARs:

regulationoflipoproteinmetabolismbyPPARa

PPARs:

regulationoflipoprot201PPARaactivatorslowersmalldenseLDLPPARaactivatorslowersmalld202AnapolipoproteinidentifiedAnapolipoproteinidentified203Plasmatriglycerideandcholesterollevels

forhumanapoA-VtransgenicmicePlasmatriglycerideandcholes204Plasmatriglycerideandcholesterollevels

forapoA-VknockoutmicePlasmatriglycerideandcholes205AllelefrequenciesforSNP3according

toplasmatriglyceridelevelsAllelefrequenciesforSNP3a206PPARaactivatorsinduceapoA-V

geneexpressio