脂代谢与动脉粥样硬化.ppt

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1、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)2.5Malaria2.1AIDS1.5Hepa

2、titis B1.2,Coronary mortality:alarming worldwide forecasts,Atherosclerosis:a multifactorial disease,Main risk factors for coronary heart disease,Global projections for the diabetes epidemic:1995-2010,Atherosclerosis,Arterial wall:structure and function,Different stages of atherosclerotic plaquedevel

3、opment,Vascular endothelium modificationin atherosclerosis,Plaque formation1 Fatty streak,Plaque formation2 Fibrous cap,Plaque formation3 Lipid core,From plaque to thrombosis,key event:plaque rupture,Lipid core constitutionActivated macrophages accumulate lipids,Lipid core constitutionLDL oxidation,

4、Parietal vascular inflammationThe activated macrophage produces inflammatory cytokines,Parietal vascular inflammationNFkB action in the inflammation process,Diabetes and atherosclerosis,Tobacco and atherosclerosis,Dyslipidemia and atherosclerosis,HTN,hemodynamic factor and atheroclerosis,How to redu

5、ce plaque formationIntervention on risk factors,How to reduce the risk of plaque rupture,How to reduce the risk of thrombosis,10%Weight loss=30%Visceraladipose tissue loss,Characteristics of an unstable plaque,Plaque vulnerability factorsIntrinsic factors,Modification of extrinsic vulnerability fact

6、ors,Plaque rupture The main releasing factors,Classification of lipids and lipoproteins,Characteristics of lipoproteins,Triglyceride-rich lipoproteins:size,structure and composition,Digestion and metabolism of dietary fat,HDL metabolism and reverse cholesterol transport,Cholesterol efflux and revers

7、e cholesteroltransport is modulated by two receptors,Atherogenicity of small dense LDL,Size and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particles,Size and apolipoprotein composition are the main factors determining atherogenicity of triglycerid

8、e-rich particles,Apo C-III modulates VLDL,Apo C-III in apo B particles is atherogenic,Relationship between apo C-III in apo Bcontaining lipoproteins and atherogenicity,PROCAM StudyMI-Incidence according to LDL-cholesterol and triglycerides,PROCAM StudyCHD risk according to LDL-C and TGincreased TG c

9、onfers raised CHD risk at all levels of LDL-C,HDL:an anti-atherogenic lipoprotein,HDL metabolism:5 key genes,HDL:apo AI-rich particles,Apo A-I protects against atherosclerosis,Apo A-II protects against atherosclerosisThe human apo A-II transgenic mouse model,Genes and environment in type 2 diabetesa

10、nd atherosclerosis,Pima IndiansThrifty genes,Aboriginal Canadians Oji-Cree,Obesity,type 2 diabetes,atherosclerosis,The Metabolic Syndrome,Visceral obesity is associated with a clusterof metabolic abnormalities,The atherogenic triad,PROCAM Study:MI-Incidence according to LDL-cholesterol and triglycer

11、ides,70%of men with CHD had a low HDL 44mg/dLFramingham Male Offspring 35-54,Obesity,type 2 diabetes,lipid metabolismThe key role of the transcriptional factors PPARs,PPARa discovery elucidatesmechanism of action of fibrates,The different PPAR subtypes,PPARa:a transcription factor,PPARa:transcriptio

12、nal activation in two stages,PPARa:transcriptional activation in two stages,Transcriptional activation by PPARa,PPARs:regulation of lipoprotein metabolism by PPARa,PPARa activators lower small dense LDL,An apolipoprotein identified,Plasma triglyceride and cholesterol levelsfor human apo A-V transgen

13、ic mice,Plasma triglyceride and cholesterol levelsfor apo A-V knockout mice,Allele frequencies for SNP 3 accordingto plasma triglyceride levels,PPARa activators induce apo A-V gene expression,PPARa activates human apo A-Vtranscription through two PPREs,PPARa:apo A-l,apo A-ll,LPL,ABCA-1 and SR-BI exp

14、ression,PPARa activators induce ABCA-1 gene expressionin human macrophages,PPARa activators induce cholesterol effluxfrom human macrophages,CLA-1/SR-BI protein may promote cholesterolremoval from peripheral cells,CLA-1 expression is regulated by PPARa activatorsin differentiated human macrophages,PP

15、ARa activators induce cholesterol effluxand reverse cholesterol transport,PPARs in the vascular wall,Mechanisms of transrepression by PPARa,The transcription factor NFkB:a key role in the inflammatory response,Model of NFkB signal pathway inhibition by PPARa activators,PPARa activated by fibrates in

16、hibits IL-1binduced expression of COX-2 in SMC,Fenofibrate reduces plasma IL-6in patients with CAD,Fenofibrate lowers plasma CRPin patients with CAD,PPARa activators reduce adhesion moleculeproduction by interfering with NFkB,PPAR activators reduce endothelin-1 productionby interfering with AP-1 tra

17、nscription factor,PPARa activators inhibit thrombin induced ET-1 secretion in human macro-and microvascular endothelial cells,PPARa activators reduce tissue factor production byinterfering with NFkB and AP-1 transcription factors,PPARa activated by fibrates negativelyregulates fibrinogen-b expressio

18、n,StatinsMolecular mechanisms of actionSREBP feedback control,SREBP*regulates the LDL receptorThree-step activation process,Common properties of PPARa activatorsand statinsParietal vascular effects,Statins and PPARa activators,similar effectsSimilar effector,PPARa?,Statins induce PPARa activity,Huma

19、n apo A-I mRNA is inducedby statins in a dose-dependent manner,Statins 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

20、gene expression,Simvastatic acid reduces inducedLPS MMP9 secretion,Parietal vascular effects of statins(1)Endothelial cells,Parietal vascular effects of statins(2)Monocytes,macrophages,PPARa activators act on the main factorsinvolved in the onset of atherosclerosis,VA-HIT,VA-HIT cont,DAIS,DAIS cont,

21、HHS,HHS cont,4S,4S cont,CARE,CARE cont,WOSCOPS,WOSCOPS cont,LIPID,LIPID cont,AFCAPS/TexCAPS,AFCAPS/TexCAPS cont,AVERT,AVERT cont,HPS,HPS cont,NCEP guidelines,NCEP guidelines cont,NCEP guidelines cont,NCEP guidelines cont,AHA/ACC guidelines,ADA guidelines,ADA guidelines cont,Lipid management for prim

22、ary prevention of CHD in adults ILIB recommendations,Lipid management for secondary prevention of CHD in adults ILIB recommendations,Lipid management for secondary prevention of CHD in adults with diabetes mellitus ILIB recommendations,Abbreviations list,AS AtherosclerosisBLBaselineBMIBody Mass Inde

23、xBPBlood 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-

24、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 Molecule

25、,IL InterleukinLCAT Lecithin Cholesterol Acetyl TransferaseLDL-CLow-Density Lipoprotein CholesterolLPL Lipoprotein Lipasemg/dMilligrams per Daymg/dLMilligrams per DeciliterMI Myocardial InfarctionNFkBNuclear Factor BNSNot SignificantPAI-1Plasminogen Activator Inhibitor Type 1PlcPlaceboPPARsPeroxisom

26、e Proliferator-Activated ReceptorsPROCAMProspective Cardiovascular Munster Study PPREResponsive ElementPTCAPercutaneous Transluminal Coronary AngiographyRXR Retinoid X ReceptorSigSignificantSREBPSterol Regulatory Element Binding ProteinTCTotal CholesterolTF Tissue FactorTG TriglycerideTNF Tumor Necr

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42、nd apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease.JAMA 1998;279;19551961.Figure 73.Fruchart JC.Are nuclear factors the ultimate targets of drugs affecting lipid metabolism?Current Atherosclerosis Reports 2000;2;353354.Figure 75,76,77 and

43、78.Pennancchio LA,Oliver M,Hubacek JA,Cohen JC,Cox DR,Fruchart JC,Krauss RM,Rubin EM.An apolipoprotein influencing triglycerides in humans and Mice revealed by comparative sequencing.Science 2001;294;169173.Figures 82 and 83.Chinetti G,Lestavel S,Bocher V,Remaley AT,Neve B,Pineda Torra I,Teissier E,

44、Minnich A,Jaye M,Duverger N,Brewer HB,Fruchart JC,Clavey V,Staels B.PPARa and PPARg activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA-1 pathway.Nature Medicine 2001;7;5358.Figure 84 and 85.Chinetti G,Baguidi G,Griglio S,Mallat Z,Antonucci M,Poulai

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46、ardiol 2001;88 supp.;24N29N.Figure 87,88,89,92,94 and 94.Staels B,Keonig W,Habib A,Merval R,Lebret M,Pineda Torra I,Delerive P,Fadel A,Chinetti G,Fruchart JC,Najib J,Maclouf J,Tedgui A.Activation of human aortic smooth-muscle cells is inhibited by PPARa but not by PPARg activators.Nature 1998;393(66

47、86);790793.Figure 90.Delerive Ph,Gervois P,Fruchart JC,Staels B.Induction of IkBa expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-a activators.J Biol Chem 2000;275/47;3670336707.Figures 95.Delerive P,Fruchart JC and Staels B.Pe

48、roxisome proliferator-activated receptors in inflammation control.J Endocrinol 2001;169;453459.Figure 96 and 97.Delerive P,Martin-Nizard F,Chinetti G,Trottein G,Fruchart JC,Najib J,Duriez P,Staels B.PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells

49、by inhibiting the activator protein-1 signaling pathway.Circ Red 1999;85;394402.Figures 98.Neve BP,Corseaux D,Chinetti G Zawadzki C,Fruchart JC,Duriez P,Staels B,Jude B.PPARa agonists inhibit tissue factor expression in human monocytes and macrophages.Circulation 2001;103;207-212.Figures 99.Gervois

50、P,Vu-Dac R,Kleeman M,Kockx M,Dubois G,Laine B,Kosykh V,Fruchart JC,Kooistra T,Staels B.Negative regulation of human fibrinogen gene expression by PPARa agonists via inhibition of C/EBPb.J Biol Chem 2001;276;3347133477.Figures 103.Schoonjans K,Peinado-Onsurbe J,Fruchart JC,Tailleux A,Fievet C,Auwerx