脂代谢与动脉粥样硬化.ppt

Cardiovascular disease is the leading causeof death among adults worldwide(1996)Coronary disease7.2 millionCancer6.3Cerebrovascular disease4.6Acute lower respiratory tract infections3.9Tuberculosis3.0COPD(chronic obstructive pulmonary disease)2.9Diarrhea(including dysentery)2.5Malaria2.1AIDS1.5Hepatitis B1.2Coronary mortality:alarming worldwide forecastsAtherosclerosis:a multifactorial diseaseMain risk factors for coronary heart diseaseGlobal projections for the diabetes epidemic:1995-2010AtherosclerosisArterial wall:structure and functionDifferent stages of atherosclerotic plaquedevelopmentVascular endothelium modificationin atherosclerosisPlaque formation1 Fatty streak Plaque formation2 Fibrous cap Plaque formation3 Lipid core From plaque to thrombosis,key event:plaque ruptureLipid core constitutionActivated macrophages accumulate lipidsLipid core constitutionLDL oxidationParietal vascular inflammationThe activated macrophage produces inflammatory cytokinesParietal vascular inflammationNFB action in the inflammation processDiabetes and atherosclerosisTobacco and atherosclerosisDyslipidemia and atherosclerosisHTN,hemodynamic factor and atheroclerosisHow to reduce plaque formationIntervention on risk factorsHow to reduce the risk of plaque ruptureHow to reduce the risk of thrombosis10%Weight loss=30%Visceraladipose tissue lossCharacteristics of an unstable plaquePlaque vulnerability factorsIntrinsic factorsModification of extrinsic vulnerability factorsPlaque rupture The main releasing factorsClassification of lipids and lipoproteinsCharacteristics of lipoproteinsTriglyceride-rich lipoproteins:size,structure and compositionDigestion and metabolism of dietary fatHDL metabolism and reverse cholesterol transportCholesterol efflux and reverse cholesteroltransport is modulated by two receptorsAtherogenicity of small dense LDLSize and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particlesSize and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particlesApo C-III modulates VLDLApo C-III in apo B particles is atherogenicRelationship between apo C-III in apo Bcontaining lipoproteins and atherogenicityPROCAM StudyMI-Incidence according to LDL-cholesterol and triglyceridesPROCAM StudyCHD risk according to LDL-C and TGincreased TG confers raised CHD risk at all levels of LDL-CHDL:an anti-atherogenic lipoproteinHDL metabolism:5 key genes HDL:apo AI-rich particlesApo A-I protects against atherosclerosisApo A-II protects against atherosclerosisThe human apo A-II transgenic mouse modelGenes and environment in type 2 diabetesand atherosclerosisPima IndiansThrifty genesAboriginal Canadians Oji-CreeObesity,type 2 diabetes,atherosclerosisThe Metabolic SyndromeVisceral obesity is associated with a clusterof metabolic abnormalitiesThe atherogenic triadPROCAM Study:MI-Incidence according to LDL-cholesterol and triglycerides70%of men with CHD had a low HDL 44mg/dLFramingham Male Offspring 35-54Obesity,type 2 diabetes,lipid metabolismThe key role of the transcriptional factors PPARsPPARa discovery elucidatesmechanism of action of fibrates The different PPAR subtypesPPARa:a transcription factorPPARa:transcriptional activation in two stagesPPARa:transcriptional activation in two stages Transcriptional activation by PPARaPPARs:regulation of lipoprotein metabolism by PPARa PPARa activators lower small dense LDLAn apolipoprotein identifiedPlasma triglyceride and cholesterol levelsfor human apo A-V transgenic micePlasma triglyceride and cholesterol levelsfor apo A-V knockout miceAllele frequencies for SNP 3 accordingto plasma triglyceride levelsPPARa activators induce apo A-V gene expressionPPARa activates human apo A-Vtranscription through two PPREsPPARa:apo A-l,apo A-ll,LPL,ABCA-1 and SR-BI expression PPARa activators induce ABCA-1 gene expressionin human macrophagesPPARa activators induce cholesterol effluxfrom human macrophagesCLA-1/SR-BI protein may promote cholesterolremoval from peripheral cellsCLA-1 expression is regulated by PPARa activatorsin differentiated human macrophagesPPARa activators induce cholesterol effluxand reverse cholesterol transportPPARs in the vascular wallMechanisms of transrepression by PPARaThe transcription factor NFB:a key role in the inflammatory responseModel of NFB signal pathway inhibition by PPARa activatorsPPARa activated by fibrates inhibits IL-1binduced expression of COX-2 in SMCFenofibrate reduces plasma IL-6in patients with CADFenofibrate lowers plasma CRPin patients with CADPPARa activators reduce adhesion moleculeproduction by interfering with NFBPPAR activators reduce endothelin-1 productionby interfering with AP-1 transcription factorPPARa activators inhibit thrombin induced ET-1 secretion in human macro-and microvascular endothelial cellsPPARa activators reduce tissue factor production byinterfering with NFB and AP-1 transcription factorsPPARa activated by fibrates negativelyregulates fibrinogen-b expressionStatinsMolecular mechanisms of actionSREBP feedback control SREBP*regulates the LDL receptorThree-step activation processCommon properties of PPARa activatorsand statinsParietal vascular effects Statins and PPARa activators,similar effectsSimilar effector,PPARa?Statins induce PPARa activityHuman apo A-I mRNA is inducedby statins in a dose-dependent mannerStatins act on apo A-I mRNA expression at the transcriptional levelInhibition by actinomycin D Statin effect on apo A-I synthesisis related to its mode of actionInhibition by mevalonate Statins and PPARa activatorsincrease human apo A-I gene expressionSimvastatic acid reduces inducedLPS MMP9 secretionParietal vascular effects of statins(1)Endothelial cellsParietal vascular effects of statins(2)Monocytes,macrophagesPPARa activators act on the main factorsinvolved in the onset of atherosclerosisVA-HITVA-HIT contDAISDAIS contHHSHHS cont4S4S contCARECARE contWOSCOPSWOSCOPS contLIPIDLIPID contAFCAPS/TexCAPSAFCAPS/TexCAPS contAVERTAVERT contHPSHPS contNCEP guidelinesNCEP guidelines contNCEP guidelines contNCEP guidelines contAHA/ACC guidelinesADA guidelinesADA guidelines contLipid management for primary prevention of CHD in adults ILIB recommendationsLipid management for secondary prevention of CHD in adults ILIB recommendationsLipid management for secondary prevention of CHD in adults with diabetes mellitus ILIB recommendationsAbbreviations listAS AtherosclerosisBLBaselineBMIBody Mass IndexBPBlood PressureCABGCoronary Artery Bypass GraftCADCoronary Artery DiseaseCARECholesterol and Recurrent EventsCE Cholesterol EsterCERPCholesterol Efflux Regulatory ProteinCETP Cholesterol Ester Transfer ProteinCHD Coronary Heart DiseaseCHFCongestive Heart FailureCholCholesterolCOX-2Cyclo-oxygenase-2CRPC Reactive ProteinCVCardiovascularCVDCardiovascular DiseaseDMDiabetes MellitusECTIM Study Etude CasTemoins de Ifarctus du MyocardeEREndoplasmic ReticulumET-1 Endothelin-1GE Glycerol EstersHDL-CHigh-Density Lipoprotein CholesterolHL Hepatic LipaseHTHypertensionICAM Intercellular Adhesion MoleculeIL InterleukinLCAT Lecithin Cholesterol Acetyl TransferaseLDL-CLow-Density Lipoprotein CholesterolLPL Lipoprotein Lipasemg/dMilligrams per Daymg/dLMilligrams per DeciliterMI Myocardial InfarctionNFBNuclear Factor BNSNot SignificantPAI-1Plasminogen Activator Inhibitor Type 1PlcPlaceboPPARsPeroxisome Proliferator-Activated ReceptorsPROCAMProspective Cardiovascular Munster Study PPREResponsive ElementPTCAPercutaneous Transluminal Coronary AngiographyRXR Retinoid X ReceptorSigSignificantSREBPSterol Regulatory Element Binding ProteinTCTotal CholesterolTF Tissue FactorTG TriglycerideTNF Tumor Necrosis FactorUAPUnstable Angina PectorisVCAM Vascular Cell Adhesion MoleculevsVersusWHRWaist Hip RatioReference listFigure 1.WHO press release based on the Director General report,1997.Figure 2.Murray CJL and Lopez AD.Evidence-based health policylessons from the Global Burden of Disease 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