脂代谢与动脉粥样硬化学习资料

脂代谢与动脉粥样硬化学习资料第1页/共137页Coronarymortality:

alarmingworldwideforecasts第2页/共137页Atherosclerosis:

amultifactorialdisease第3页/共137页Mainriskfactorsforcoronaryheartdisease第4页/共137页Globalprojectionsforthediabetesepidemic:

1995-2010第5页/共137页Atherosclerosis第6页/共137页Arterialwall:

structureandfunction第7页/共137页Differentstagesofatheroscleroticplaque

development第8页/共137页Vascularendotheliummodification

inatherosclerosis第9页/共137页Plaqueformation

1—Fattystreak

第10页/共137页Plaqueformation

2—Fibrouscap

第11页/共137页Plaqueformation

3—Lipidcore

第12页/共137页Fromplaquetothrombosis,keyevent:

plaquerupture第13页/共137页Lipidcoreconstitution

Activatedmacrophagesaccumulatelipids第14页/共137页Lipidcoreconstitution

LDLoxidation第15页/共137页Parietalvascularinflammation

Theactivatedmacrophageproducesinflammatorycytokines第16页/共137页

Parietalvascularinflammation

NFkBactionintheinflammationprocess

第17页/共137页Diabetesandatherosclerosis第18页/共137页Tobaccoandatherosclerosis第19页/共137页Dyslipidemiaandatherosclerosis第20页/共137页HTN,hemodynamicfactorandatheroclerosis第21页/共137页Howtoreduceplaqueformation

Interventiononriskfactors第22页/共137页Howtoreducetheriskofplaquerupture第23页/共137页Howtoreducetheriskofthrombosis第24页/共137页~10%Weightloss=~30%Visceral

adiposetissueloss第25页/共137页Characteristicsofanunstableplaque第26页/共137页Plaquevulnerabilityfactors

Intrinsicfactors第27页/共137页Modificationofextrinsicvulnerabilityfactors第28页/共137页

Plaquerupture

Themainreleasingfactors

第29页/共137页Classificationoflipidsandlipoproteins第30页/共137页Characteristicsoflipoproteins第31页/共137页Triglyceride-richlipoproteins:

size,structureandcomposition第32页/共137页Digestionandmetabolismofdietaryfat第33页/共137页HDLmetabolismandreversecholesteroltransport第34页/共137页Cholesteroleffluxandreversecholesterol

transportismodulatedbytworeceptors第35页/共137页AtherogenicityofsmalldenseLDL第36页/共137页Sizeandapolipoproteincompositionarethemainfactorsdeterminingatherogenicityoftriglyceride-richparticles第37页/共137页Sizeandapolipoproteincompositionarethemainfactorsdeterminingatherogenicityoftriglyceride-richparticles第38页/共137页ApoC-IIImodulatesVLDL第39页/共137页ApoC-IIIinapoBparticlesisatherogenic第40页/共137页RelationshipbetweenapoC-IIIinapoB

containinglipoproteinsandatherogenicity第41页/共137页PROCAMStudy

MI-IncidenceaccordingtoLDL-cholesterolandtriglycerides第42页/共137页PROCAMStudy

CHDriskaccordingtoLDL-CandTG

increasedTGconfersraisedCHDriskatalllevelsofLDL-C第43页/共137页HDL:

ananti-atherogeniclipoprotein第44页/共137页HDLmetabolism:

5keygenes

第45页/共137页HDL:

apoAI-richparticles第46页/共137页ApoA-Iprotectsagainstatherosclerosis第47页/共137页ApoA-IIprotectsagainstatherosclerosis

ThehumanapoA-IItransgenicmousemodel第48页/共137页Genesandenvironmentintype2diabetes

andatherosclerosis第49页/共137页PimaIndians

Thriftygenes第50页/共137页AboriginalCanadiansOji-Cree第51页/共137页Obesity,type2diabetes,atherosclerosis第52页/共137页TheMetabolicSyndrome第53页/共137页Visceralobesityisassociatedwithacluster

ofmetabolicabnormalities第54页/共137页Theatherogenictriad第55页/共137页PROCAMStudy:

MI-IncidenceaccordingtoLDL-cholesterolandtriglycerides第56页/共137页70%ofmenwithCHDhadalowHDL≤44mg/dL

FraminghamMaleOffspring35-54第57页/共137页Obesity,type2diabetes,lipidmetabolism

ThekeyroleofthetranscriptionalfactorsPPARs第58页/共137页

PPARadiscoveryelucidates

mechanismofactionoffibrates

第59页/共137页ThedifferentPPARsubtypes第60页/共137页PPARa:

atranscriptionfactor第61页/共137页PPARa:

transcriptionalactivationintwostages第62页/共137页PPARa:

transcriptionalactivationintwostages

第63页/共137页TranscriptionalactivationbyPPARa第64页/共137页

PPARs:

regulationoflipoproteinmetabolismbyPPARa

第65页/共137页PPARaactivatorslowersmalldenseLDL第66页/共137页Anapolipoproteinidentified第67页/共137页Plasmatriglycerideandcholesterollevels

forhumanapoA-Vtransgenicmice第68页/共137页Plasmatriglycerideandcholesterollevels

forapoA-Vknockoutmice第69页/共137页AllelefrequenciesforSNP3according

toplasmatriglyceridelevels第70页/共137页PPARaactivatorsinduceapoA-V

geneexpression第71页/共137页PPARaactivateshumanapoA-V

transcriptionthroughtwoPPREs第72页/共137页

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

ABCA-1andSR-BIexpression

第73页/共137页PPARaactivatorsinduceABCA-1geneexpression

inhumanmacrophages第74页/共137页PPARaactivatorsinducecholesterolefflux

fromhumanmacrophages第75页/共137页CLA-1/SR-BIproteinmaypromotecholesterol

removalfromperipheralcells第76页/共137页CLA-1expressionisregulatedbyPPARaactivators

indifferentiatedhumanmacrophages第77页/共137页PPARaactivatorsinducecholesterolefflux

andreversecholesteroltransport第78页/共137页PPARsinthevascularwall第79页/共137页MechanismsoftransrepressionbyPPARa第80页/共137页ThetranscriptionfactorNFkB:

akeyroleintheinflammatoryresponse第81页/共137页ModelofNFkBsignalpathwayinhibition

byPPARaactivators第82页/共137页PPARaactivatedbyfibratesinhibitsIL-1b

inducedexpressionofCOX-2inSMC第83页/共137页

FenofibratereducesplasmaIL-6

inpatientswithCAD

第84页/共137页

FenofibratelowersplasmaCRP

inpatientswithCAD

第85页/共137页PPARaactivatorsreduceadhesionmolecule

productionbyinterferingwithNFkB第86页/共137页PPARactivatorsreduceendothelin-1production

byinterferingwithAP-1transcriptionfactor第87页/共137页PPARaactivatorsinhibitthrombininducedET-1secretioninhumanmacro-andmicrovascularendothelialcells第88页/共137页PPARaactivatorsreducetissuefactorproductionby

interferingwithNFkBandAP-1transcriptionfactors第89页/共137页PPARaactivatedbyfibratesnegatively

regulatesfibrinogen-bexpression第90页/共137页Statins

Molecularmechanismsofaction

SREBPfeedbackcontrol

第91页/共137页SREBP*regulatestheLDLreceptor

Three-stepactivationprocess第92页/共137页CommonpropertiesofPPARaactivators

andstatins

Parietalvasculareffects

第93页/共137页StatinsandPPARaactivators,similareffects

Similareffector,PPARa?

第94页/共137页StatinsinducePPARaactivity第95页/共137页HumanapoA-ImRNAisinduced

bystatinsinadose-dependentmanner第96页/共137页StatinsactonapoA-ImRNA

expressionatthetranscriptionallevel

InhibitionbyactinomycinD

第97页/共137页StatineffectonapoA-Isynthesis

isrelatedtoitsmodeofaction

Inhibitionbymevalonate

第98页/共137页StatinsandPPARaactivators

increasehumanapoA-Igeneexpression第99页/共137页Simvastaticacidreducesinduced

LPSMMP9secretion第100页/共137页Parietalvasculareffectsofstatins(1)

Endothelialcells第101页/共137页Parietalvasculareffectsofstatins(2)

Monocytes,macrophages第102页/共137页PPARaactivatorsactonthemainfactors

involvedintheonsetofatherosclerosis第103页/共137页

VA-HIT第104页/共137页VA-HITcont第105页/共137页

DAIS第106页/共137页

DAIScont第107页/共137页

HHS第108页/共137页HHScont第109页/共137页

4S第110页/共137页

4Scont第111页/共137页

CARE第112页/共137页

CAREcont第113页/共137页

WOSCOPS第114页/共137页

WOSCOPScont第115页/共137页

LIPID第116页/共137页

LIPIDcont第117页/共137页

AFCAPS/TexCAPS第118页/共137页

AFCAPS/TexCAPScont第119页/共137页

AVERT第120页/共137页

AVERTcont第121页/共137页

HPS第122页/共137页

HPScont第123页/共137页

NCEPguidelines第124页/共137页

NCEPguidelinescont第125页/共137页

NCEPguidelinescont第126页/共137页

NCEPguidelinescont第127页/共137页

AHA/ACCguidelines第128页/共137页

ADAguidelines第129页/共137页

ADAguidelinescont第130页/共137页

LipidmanagementforprimarypreventionofCHD

inadults–ILIBrecommendations

第131页/共137页

LipidmanagementforsecondarypreventionofCHD

inadults–ILIBrecommendations

第132页/共137页

LipidmanagementforsecondarypreventionofCHD

inadultswithdiabetesmellitus–ILIBrecommendations

第133页/共137页

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第134页/共137页

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