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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.EndotheliumEndotheliumVessel LumenVessel LumenIntimaIntimaFoam CellFoam CellMonocyteMonocyteCytokinesCytokinesGrowth FactorsGrowth FactorsMetalloproteinasesMetalloproteinasesCell ProliferationCell ProliferationMatrix DegradationMatrix DegradationMacrophageMacrophageAtherosclerosis 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.HDLHDLLDLLDLChylomicrons,Chylomicrons,VLDL,and VLDL,and their catabolic their catabolic remnantsremnants 30 nm 30 nm2022 nm2022 nmPotentially proinflammatoryPotentially proinflammatory915 nm915 nmPotentially anti-Potentially anti-inflammatoryinflammatoryLipoprotein Classes and InflamStructure of LDLMurphy HC et al.Biochemistry 2000;39:9763-970.Hydrophobic CoreHydrophobic Core of Triglyceride and of Triglyceride and Cholesteryl EstersCholesteryl EstersapoBapoBSurface Monolayer Surface Monolayer of Phospholipids of Phospholipids and Free and Free CholesterolCholesterolStructure of LDLMurphy HC et aRole of LDL in InflammationSteinberg D et al.N Engl J Med 1989;320:915-924.EndotheliumEndotheliumVessel LumenVessel LumenLDLLDLLDL Readily Enter the Artery Wall Where They May be ModifiedLDL Readily Enter the Artery Wall Where They May be ModifiedLDLLDLIntimaIntimaModified LDLModified LDLModified LDL are ProinflammatoryModified LDL are ProinflammatoryHydrolysis of PhosphatidylcholineHydrolysis of Phosphatidylcholineto Lysophosphatidylcholineto LysophosphatidylcholineOther Chemical ModificationsOther Chemical ModificationsOxidation of LipidsOxidation of Lipidsand ApoBand ApoBAggregationAggregationRole of LDL in InflammationSteLDLLDLLDLLDLModified LDL Stimulate Expression of MCP-1 in Endothelial CellsNavab M et al.J Clin Invest 1991;88:2039-2046.EndotheliumEndotheliumVessel LumenVessel LumenIntimaIntimaMonocyteMonocyteModified LDLModified LDLMCP-1MCP-1LDLLDLModified LDL Stimulate ELDLLDLLDLLDLDifferentiation of Monocytes into MacrophagesSteinberg D et al.N Engl J Med 1989;320:915-924.EndotheliumEndotheliumVessel LumenVessel LumenIntimaIntimaMonocyteMonocyteModified LDLModified LDLModified LDL PromoteModified LDL PromoteDifferentiation ofDifferentiation ofMonocytes intoMonocytes intoMacrophagesMacrophagesMCP-1MCP-1MacrophageMacrophageLDLLDLDifferentiation of MonocLDLLDLLDLLDLModified LDL Induces Macrophages to Release Cytokines Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Expression in That Stimulate Adhesion Molecule Expression in Endothelial CellsEndothelial CellsNathan CF.J Clin Invest 1987;79:319-326.EndotheliumEndotheliumVessel LumenVessel LumenMonocyteMonocyteModified LDLModified LDLMacrophageMacrophageMCP-1MCP-1AdhesionAdhesionMoleculesMoleculesCytokinesCytokinesIntimaIntimaLDLLDLModified LDL Induces MacLDLLDLLDLLDLEndotheliumEndotheliumVessel LumenVessel LumenMonocyteMonocyteMacrophageMacrophageMCP-1MCP-1AdhesionAdhesionMoleculesMoleculesSteinberg D et al.N Engl J Med 1989;320:915-924.Macrophages Express Receptors That Take up Modified LDLFoam CellFoam CellModified LDL Modified LDL Taken up by Taken up by MacrophageMacrophageIntimaIntimaLDLLDLEndotheliumVessel LumenMLDLLDLLDLLDLEndotheliumEndotheliumVessel LumenVessel LumenMonocyteMonocyteMacrophageMacrophageAdhesionAdhesionMoleculesMoleculesMacrophages and Foam Cells Express Growth Factors and ProteinasesFoam CellFoam CellIntimaIntimaModified Modified LDLLDLCytokinesCytokinesCell ProliferationCell ProliferationMatrix DegradationMatrix DegradationGrowth FactorsGrowth FactorsMetalloproteinasesMetalloproteinasesRoss R.N Engl J Med 1999;340:115-126.MCP-1MCP-1MCP-1LDLLDLEndotheliumVessel LumenMEndotheliumEndotheliumVessel LumenVessel LumenMonocyteMonocyteMacrophageMacrophageMCP-1MCP-1MCP-1AdhesionAdhesionMoleculesMoleculesThe Remnants of VLDL and Chylomicrons are Also ProinflammatoryFoam CellFoam CellIntimaIntimaModifiedModifiedRemnantsRemnantsCytokinesCytokinesCell ProliferationCell ProliferationMatrix DegradationMatrix DegradationDoi H et al.Circulation 2000;102:670-676.Growth FactorsGrowth FactorsMetalloproteinasesMetalloproteinasesRemnant LipoproteinsRemnant LipoproteinsRemnantsRemnantsEndotheliumVessel LumenMonocytStructure of HDLRye KA et al.Atherosclerosis 1999;145:227-238.Hydrophobic CoreHydrophobic Core of Triglyceride and of Triglyceride and Cholesteryl EstersCholesteryl EstersapoA-IIapoA-IISurface Monolayer Surface Monolayer of Phospholipids of Phospholipids and Free and Free CholesterolCholesterolapoA-IapoA-IStructure of HDLRye KA et al.LDLLDLLDLLDLMiyazaki A et al.Biochim Biophys Acta 1992;1126:73-80.EndotheliumEndotheliumVessel LumenVessel LumenMonocyteMonocyteModified LDLModified LDLMacrophageMacrophageMCP-1MCP-1AdhesionAdhesionMoleculesMoleculesCytokinesCytokinesHDL Prevent Formation of Foam CellsIntimaIntimaHDL Promote Cholesterol EffluxHDL Promote Cholesterol EffluxFoam Foam CellCellLDLLDLMiyazaki A et al.BiochiLDLLDLLDLLDLMackness MI et al.Biochem J 1993;294:829-834.EndotheliumEndotheliumVessel LumenVessel LumenMonocyteMonocyteModified LDLModified LDLMacrophageMacrophageMCP-1MCP-1AdhesionAdhesionMoleculesMoleculesCytokinesCytokinesHDL Inhibit the Oxidative Modification of LDLHDL Inhibit the Oxidative Modification of LDLFoam Foam CellCellHDL Promote Cholesterol EffluxHDL Promote Cholesterol EffluxIntimaIntimaHDL InhibitHDL InhibitOxidationOxidationof LDLof LDLLDLLDLMackness MI et al.BiochInhibition of LDL Oxidation by HDL:Role of ParaoxonasenParaoxonase is transported in plasma as a component of HDLnParaoxonase is known to inhibit the oxidative modification of LDLnThus,the presence of paraoxonase in HDL may account for a proportion 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 LDLnCETP transfers oxidized lipids from LDL to HDLnThe oxidized lipids in HDL are reduced by HDL apolipoproteinsnThe 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 inLDLLDLLDLLDLCockerill GW et al.Arterioscler Thromb Vasc Biol 1995;15:1987-1994.EndotheliumEndotheliumVessel LumenVessel LumenMonocyteMonocyteModified LDLModified LDLMacrophageMacrophageMCP-1MCP-1AdhesionAdhesionMoleculesMoleculesCytokinesCytokinesInhibition of Adhesion MoleculesIntimaIntimaHDL InhibitHDL InhibitOxidationOxidationof LDLof LDLHDL Inhibit Adhesion Molecule ExpressionHDL Inhibit Adhesion Molecule ExpressionFoam Foam CellCellHDL Promote Cholesterol EffluxHDL Promote Cholesterol EffluxLDLLDLCockerill GW et al.ArteEndotheliumEndotheliumVessel LumenVessel LumenMCP-1MCP-1E-SelectinE-SelectinCharo IF.Curr Opin Lipidol 1992;3:335-343.Recruitment of Blood Monocytes by Endothelial Cell Adhesion MoleculesIntimaIntimaVCAM-1VCAM-1ICAM-1ICAM-1StickingStickingMonocyteMonocyteRollingRollingTransmigrationTransmigrationEndotheliumVessel LumenMCP-1E-HDL Inhibit Endothelial Cell Sphingosine KinaseXia P et al.J Biol Chem 1999;274:33143-33147.SphingomyelinSphingomyelinCeramideCeramideSphingosineSphingosineSph-1-PSph-1-PHDLNF-NF-KKB BAdhesion Protein Adhesion Protein SynthesisSynthesisSM-aseSM-aseSph KinaseSph Kinase+TNFXHDL Inhibit Endothelial Cell SHeterogeneity of HDLRye KA et al.Atherosclerosis 1999;145:227-238.Apolipoprotein CompositionApolipoprotein CompositionA-I HDLA-I HDLA-I/A-II HDLA-I/A-II HDLA-II HDLA-II HDLParticle ShapeParticle ShapeDiscoidalDiscoidalSphericalSphericalLipid CompositionLipid CompositionTG,CE,and PLTG,CE,and PLParticle SizeParticle SizeHDLHDL2b2bHDLHDL2a2aHDLHDL3a3aHDLHDL3b3bHDLHDL3c3cHeterogeneity of HDLRye KA et Inhibition of Endothelial Cell VCAM-1 Expression by HDL:Effect of HDL CompositionnInhibition unaffected by replacing apoA-I with apoA-IInInhibition unaffected by replacing apoA-I with SAAnInhibition unaffected by varying the cholesteryl ester or triglyceride content of HDLnInhibition ISIS 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 HDLPhosphatidylcholine Composition of Human HDLPO=1-palmitoyl-2-oleoyl-;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 control)Baker PW et al.J Lipid Res 2000;41:1261-1267.Inhibition of Endothelial Cell VCAM-1 Expression Inhibition of Endothelial Cell VCAM-1 Expression by HDL:by HDL:Effect of HDL Phospholipid CompositionEffect of HDL Phospholipid Composition POPC02468PAPCPLPCrHDL Particle Molarity(mM)PL=1-palmitoyl-2-linoleoyl-;PA=1-palmitoyl-2-arachidonyl-;PO=1-palmitoyl-2-oleoyl-;rHDL=reconstituted HDLVCAM-1 Expression(%of controAdditional Anti-inflammatory Properties of HDLnHDL bind and neutralize proinflammatory lipopolysaccharidesnThe 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 et al.Proc Natl Acad Sci U S A 1977;74:4025-4028.Additional Anti-inflammatory PAnimal StudiesnIncreasing the concentration of LDL or remnant particles in animal models results in expression of endothelial cell adhesion molecules at the sites where atherosclerotic lesions developnInfusion or overexpression 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;Theilmeier G et al.FASEB J 2000;14:2032-2039.Animal StudiesIncreasing the cStudies in HumansnTreatments that reduce the level of LDL reduce the plasma levels of C-reactive protein and soluble adhesion molecules BUTnThese effects may represent pleiotropic effects of lipid-modifying agents and be unrelated to the changes in lipoprotein levelsRidker PM et al.Ridker PM et al.CirculationCirculation 1998;98:839-844;Hackman A et al.1998;98:839-844;Hackman A et al.CirculationCirculation 1996;93:1334-1338.1996;93:1334-1338.Studies in HumansTreatments thSummarynThe evidence that atherosclerosis is an inflammatory disorder is overwhelmingnLDL are subject to proinflammatory modifications that may account for their atherogenicitynHDL have anti-inflammatory properties that may contribute to their ability to protect against atherosclerosisSummaryThe evidence that atherConclusionsnStrategies that reduce proinflammatory modifications to LDL may reduce atherosclerosisnStrategies that increase the anti-inflammatory properties of HDL may also reduce atherosclerosisnMore research is needed to determine whether pharmacological increases in HDL are anti-inflammatory and reduce atherosclerosisConclusionsStrategies that red谢谢您的聆听与观看THANK YOU FOR YOUR GUIDANCE.感谢阅读！为了方便学习和使用，本文档的内容可以在下载后随意修改，调整和打印。欢迎下载！汇报人：XXX日期：20XX年XX月XX日谢谢您的聆听与观看THANK YOU FOR YOUR GU
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