脂蛋白在动脉粥样硬化炎症中的作用优选课件

1、Role of Lipoproteins in InflammationPhilip Barter and Kerry-Anne RyeRole of Lipoproteins in InflamAtherosclerosis is an Inflammatory DiseaseRoss R. N Engl J Med 1999;340:115-126.EndotheliumVessel LumenIntimaFoam CellMonocyteCytokinesGrowth FactorsMetalloproteinasesCell ProliferationMatrix Degradatio

2、nMacrophageAtherosclerosis is an InflammaLipoprotein Classes and InflammationDoi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.HDLLDLChylomicrons,VLDL, and their catabolic remnants 30 nm202

3、2 nmPotentially proinflammatory915 nmPotentially anti- inflammatoryLipoprotein Classes and InflamStructure of LDLMurphy HC et al. Biochemistry 2000;39:9763-970.Hydrophobic Core of Triglyceride and Cholesteryl EstersapoBSurface Monolayer of Phospholipids and Free CholesterolStructure of LDLMurphy HC

4、et aRole of LDL in InflammationSteinberg D et al. N Engl J Med 1989;320:915-924.EndotheliumVessel LumenLDLLDL Readily Enter the Artery Wall Where They May be ModifiedLDLIntimaModified LDLModified LDL are ProinflammatoryHydrolysis of Phosphatidylcholineto LysophosphatidylcholineOther Chemical Modific

5、ationsOxidation of Lipidsand ApoBAggregationRole of LDL in InflammationSteLDLLDLModified LDL Stimulate Expression of MCP-1 in Endothelial CellsNavab M et al. J Clin Invest 1991;88:2039-2046.EndotheliumVessel LumenIntimaMonocyteModified LDLMCP-1LDLLDLModified LDL Stimulate ELDLLDLDifferentiation of M

6、onocytes into MacrophagesSteinberg D et al. N Engl J Med 1989;320:915-924.EndotheliumVessel LumenIntimaMonocyteModified LDLModified LDL PromoteDifferentiation ofMonocytes intoMacrophagesMCP-1MacrophageLDLLDLDifferentiation of MonocLDLLDLModified LDL Induces Macrophages to Release Cytokines That Stim

7、ulate Adhesion Molecule Expression in Endothelial CellsNathan CF. J Clin Invest 1987;79:319-326.EndotheliumVessel LumenMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesIntimaLDLLDLModified LDL Induces MacLDLLDLEndotheliumVessel LumenMonocyteMacrophageMCP-1AdhesionMoleculesSteinberg D et

8、al. N Engl J Med 1989;320:915-924.Macrophages Express Receptors That Take up Modified LDLFoam CellModified LDL Taken up by MacrophageIntimaLDLLDLEndotheliumVessel LumenMLDLLDLEndotheliumVessel LumenMonocyteMacrophageAdhesionMoleculesMacrophages and Foam Cells Express Growth Factors and ProteinasesFo

9、am CellIntimaModified LDLCytokinesCell ProliferationMatrix DegradationGrowth FactorsMetalloproteinasesRoss R. N Engl J Med 1999;340:115-126.MCP-1LDLLDLEndotheliumVessel LumenMEndotheliumVessel LumenMonocyteMacrophageMCP-1AdhesionMoleculesThe Remnants of VLDL and Chylomicrons are Also Proinflammatory

10、Foam CellIntimaModifiedRemnantsCytokinesCell ProliferationMatrix DegradationDoi H et al. Circulation 2000;102:670-676.Growth FactorsMetalloproteinasesRemnant LipoproteinsRemnantsEndotheliumVessel LumenMonocytStructure of HDLRye KA et al. Atherosclerosis 1999;145:227-238.Hydrophobic Core of Triglycer

11、ide and Cholesteryl EstersapoA-IISurface Monolayer of Phospholipids and Free CholesterolapoA-IStructure of HDLRye KA et al. LDLLDLMiyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.EndotheliumVessel LumenMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesHDL Prevent Formation of Foam C

12、ellsIntimaHDL Promote Cholesterol EffluxFoam CellLDLLDLMiyazaki A et al. BiochiLDLLDLMackness MI et al. Biochem J 1993;294:829-834.EndotheliumVessel LumenMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesHDL Inhibit the Oxidative Modification of LDLFoam CellHDL Promote Cholesterol EffluxI

13、ntimaHDL InhibitOxidationof LDLLDLLDLMackness MI et al. BiochInhibition of LDL Oxidation by HDL:Role of ParaoxonaseParaoxonase is transported in plasma as a component of HDLParaoxonase is known to inhibit the oxidative modification of LDLThus, the presence of paraoxonase in HDL may account for a pro

14、portion of the antioxidant properties of these lipoproteinsMackness MI et al. FEBS Lett 1991;286:152-154.Inhibition of LDL Oxidation byRole of HDL Apolipoproteins in Removing Oxidized Lipids from LDLCETP transfers oxidized lipids from LDL to HDLThe oxidized lipids in HDL are reduced by HDL apolipopr

15、oteinsThe liver takes up reduced lipids from HDL more rapidly than from LDLChristison JK et al. J Lipid Res 1995;36:2017-2026; Gardner B et al. J Biol Chem 1998;273:6088-6095.Role of HDL Apolipoproteins inLDLLDLCockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.EndotheliumVessel Lum

16、enMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesInhibition of Adhesion MoleculesIntimaHDL InhibitOxidationof LDLHDL Inhibit Adhesion Molecule ExpressionFoam CellHDL Promote Cholesterol EffluxLDLLDLCockerill GW et al. ArteEndotheliumVessel LumenMCP-1E-SelectinCharo IF. Curr Opin Lipido

17、l 1992;3:335-343.Recruitment of Blood Monocytes by Endothelial Cell Adhesion MoleculesIntimaVCAM-1ICAM-1StickingMonocyteRollingTransmigrationEndotheliumVessel LumenMCP-1E-HDL Inhibit Endothelial Cell Sphingosine KinaseXia P et al. J Biol Chem 1999;274:33143-33147.SphingomyelinCeramideSphingosineSph-

18、1-PHDLNF-KBAdhesion Protein SynthesisSM-aseSph Kinase+TNFXHDL Inhibit Endothelial Cell SHeterogeneity of HDLRye KA et al. Atherosclerosis 1999;145:227-238.Apolipoprotein CompositionA-I HDLA-I/A-II HDLA-II HDLParticle ShapeDiscoidalSphericalLipid CompositionTG, CE, and PLParticle SizeHDL2bHDL2aHDL3aH

19、DL3bHDL3cHeterogeneity of HDLRye KA et Inhibition of Endothelial Cell VCAM-1 Expression by HDL: Effect of HDL CompositionInhibition unaffected by replacing apoA-I with apoA-IIInhibition unaffected by replacing apoA-I with SAAInhibition unaffected by varying the cholesteryl ester or triglyceride cont

20、ent of HDLInhibition IS affected by varying HDL phospholipidsBaker PW et al. J Lipid Res 1999;40:345-353.Inhibition of Endothelial CellFatty Acyl Moiety in Position% OccurrenceSubbaiah PV et al. Biochim Biophys Acta 1989;1003:145-150.Phosphatidylcholine Composition of Human HDLPO = 1-palmitoyl-2-ole

21、oyl-; PL = 1-palmitoyl-2-linoleoyl-; PA = 1-palmitoyl-2-arachidonyl-Fatty Acyl Moiety in Position16:018:118:220:320:420:522:618:118:220:320:420:518:118:220:420:518:216:018:018:118:2POPC, PLPC and PAPC account for 55% of all PC molecular speciesPOPLPAFatty Acyl Moiety in PositioVCAM-1 Expression(% of

22、 control)Baker PW et al. J Lipid Res 2000;41:1261-1267.Inhibition of Endothelial Cell VCAM-1 Expression by HDL: Effect of HDL Phospholipid Composition POPC02468PAPCPLPCrHDL Particle Molarity (mM)PL = 1-palmitoyl-2-linoleoyl-; PA = 1-palmitoyl-2-arachidonyl-; PO = 1-palmitoyl-2-oleoyl-; rHDL = recons

23、tituted HDLVCAM-1 Expression(% of controAdditional Anti-inflammatory Properties of HDLHDL bind and neutralize proinflammatory lipopolysaccharidesThe acute phase reactant SAA binds to plasma HDL, which possibly neutralizes the effects of SAABaumberger C et al. Pathobiology 1991;59:378-383; Benditt EP

24、 et al. Proc Natl Acad Sci U S A 1977;74:4025-4028.Additional Anti-inflammatory PAnimal StudiesIncreasing the concentration of LDL or remnant particles in animal models results in expression of endothelial cell adhesion molecules at the sites where atherosclerotic lesions developInfusion or overexpr

25、ession of apoA-I in animal models reduces oxidation of LDL and reduces endothelial cell adhesion molecule expressionSakai A et al. Arterioscler Thromb Vasc Biol 1997;17:310-316; Dimayuga P et al. Biochem Biophys Res Commun 1999;264:465-468; Cockerill GW et al. Circulation 2001;103:108-112; Theilmeie

26、r G et al. FASEB J 2000;14:2032-2039.Animal StudiesIncreasing the cStudies in HumansTreatments that reduce the level of LDL reduce the plasma levels of C-reactive protein and soluble adhesion molecules BUTThese effects may represent pleiotropic effects of lipid-modifying agents and be unrelated to the changes in lipoprotein levelsRidker PM et al. Circulation 1998;98:839-84