该幻灯为CME系列幻灯之一，作者为著名的动脉粥样硬化研究专家Philip Barter教授，主要探讨了脂蛋白（特别是ox-LDL和HDL）在动脉粥样硬化炎症中的作用，制作精美。
Role of Lipoproteins in Inflammation Philip Barter and Kerry-Anne Rye
Atherosclerosis is an Inflammatory Disease
Ross R. N Engl J Med 1999;340:115-126.
Endothelium
Vessel Lumen
Intima
Foam Cell
Monocyte
Cytokines
Growth Factors
Metalloproteinases
Cell Proliferation Matrix Degradation
Macrophage
Lipoprotein Classes and Inflammation
Doi 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.
HDL
LDL
Chylomicrons, VLDL, and their catabolic remnants
> 30 nm
20–22 nm
Potentially proinflammatory
9–15 nm
Potentially anti- inflammatory
Structure of LDL
Murphy HC et al. Biochemistry 2000;39:9763-970.
Hydrophobic Core of Triglyceride and Cholesteryl Esters
apoB
Surface Monolayer of Phospholipids and Free Cholesterol
Role of LDL in Inflammation
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel Lumen
LDL
LDL Readily Enter the Artery Wall Where They May be Modified
LDL
Intima
Modified LDL
Modified LDL are Proinflammatory
Hydrolysis of Phosphatidylcholine to Lysophosphatidylcholine
Other Chemical Modifications
Oxidation of Lipids and ApoB
Aggregation
LDL
LDL
Modified LDL Stimulate Expression of MCP-1 in Endothelial Cells
Navab M et al. J Clin Invest 1991;88:2039-2046.
Endothelium
Vessel Lumen
Intima
Monocyte
Modified LDL
MCP-1
LDL
LDL
Differentiation of Monocytes into Macrophages
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel Lumen
Intima
Monocyte
Modified LDL
Modified LDL Promote Differentiation of Monocytes into Macrophages
MCP-1
Macrophage
LDL
LDL
Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Expression in Endothelial Cells
Nathan CF. J Clin Invest 1987;79:319-326.
Endothelium
Vessel Lumen
Monocyte
Modified LDL
Macrophage
MCP-1
Adhesion Molecules
Cytokines
Intima
LDL
LDL
Endothelium
Vessel Lumen
Monocyte
Macrophage
MCP-1
Adhesion Molecules
Steinberg D et al. N Engl J Med 1989;320:915-924.
Macrophages Express Receptors That Take up Modified LDL
Foam Cell
Modified LDL Taken up by Macrophage
Intima
LDL
LDL
Endothelium
Vessel Lumen
Monocyte
Macrophage
Adhesion Molecules
Macrophages and Foam Cells Express Growth Factors and Proteinases
Foam Cell
Intima
Modified LDL
Cytokines
Cell Proliferation Matrix Degradation
Growth Factors Metalloproteinases
Ross R. N Engl J Med 1999;340:115-126.
MCP-1
Endothelium
Vessel Lumen
Monocyte
Macrophage
MCP-1
Adhesion Molecules
The Remnants of VLDL and Chylomicrons are Also Proinflammatory
Foam Cell
Intima
Modified Remnants
Cytokines
Cell Proliferation Matrix Degradation
Doi H et al. Circulation 2000;102:670-676.
Growth Factors Metalloproteinases
Remnant Lipoproteins
Remnants
Structure of HDL
Rye KA et al. Atherosclerosis 1999;145:227-238.
Hydrophobic Core of Triglyceride and Cholesteryl Esters
apoA-II
Surface Monolayer of Phospholipids and Free Cholesterol
apoA-I
LDL
LDL
Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.
Endothelium
Vessel Lumen
Monocyte
Modified LDL
Macrophage
MCP-1
Adhesion Molecules
Cytokines
HDL Prevent Formation of Foam Cells
Intima
HDL Promote Cholesterol Efflux
Foam Cell
LDL
LDL
Mackness MI et al. Biochem J 1993;294:829-834.
Endothelium
Vessel Lumen
Monocyte
Modified LDL
Macrophage
MCP-1
Adhesion Molecules
Cytokines
HDL Inhibit the Oxidative Modification of LDL
Foam Cell
HDL Promote Cholesterol Efflux
Intima
HDL Inhibit Oxidation of LDL
Inhibition of LDL Oxidation by HDL: Role of Paraoxonase
Paraoxonase is transported in plasma as a component of HDL
Paraoxonase is known to inhibit the oxidative modification of LDL
Thus, the presence of paraoxonase in HDL may account for a proportion of the antioxidant properties of these lipoproteins
Mackness MI et al. FEBS Lett 1991;286:152-154.
Role of HDL Apolipoproteins in Removing Oxidized Lipids from LDL
CETP transfers oxidized lipids from LDL to HDL
The oxidized lipids in HDL are reduced by HDL apolipoproteins
The liver takes up reduced lipids from HDL more rapidly than from LDL
Christison JK et al. J Lipid Res 1995;36:2017-2026; Gardner B et al. J Biol Chem 1998;273:6088-6095.
LDL
LDL
Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
Endothelium
Vessel Lumen
Monocyte
Modified LDL
Macrophage
MCP-1
Adhesion Molecules
Cytokines
Inhibition of Adhesion Molecules
Intima
HDL Inhibit Oxidation of LDL
HDL Inhibit Adhesion Molecule Expression
Foam Cell
HDL Promote Cholesterol Efflux
Endothelium
Vessel Lumen
MCP-1
E-Selectin
Charo IF. Curr Opin Lipidol 1992;3:335-343.
Recruitment of Blood Monocytes by Endothelial Cell Adhesion Molecules
Intima
VCAM-1
ICAM-1
Sticking
Monocyte
Rolling
Transmigration
HDL Inhibit Endothelial Cell Sphingosine Kinase
Xia P et al. J Biol Chem 1999;274:33143-33147.
Sphingomyelin
Ceramide
Sphingosine
Sph-1-P
HDL
NF-KB
Adhesion Protein Synthesis
SM-ase
Sph Kinase
+
TNF?
X
Heterogeneity of HDL
Rye KA et al. Atherosclerosis 1999;145:227-238.
Apolipoprotein Composition
A-I HDL
A-I/A-II HDL
A-II HDL
Particle Shape
Discoidal
Spherical
Lipid Composition
TG, CE, and PL
Particle Size
HDL2b
HDL2a
HDL3a
HDL3b
HDL3c
Inhibition of Endothelial Cell VCAM-1 Expression by HDL: Effect of HDL Composition
Inhibition unaffected by replacing apoA-I with apoA-II
Inhibition unaffected by replacing apoA-I with SAA
Inhibition unaffected by varying the cholesteryl ester or triglyceride content of HDL
Inhibition IS affected by varying HDL phospholipids
Baker PW et al. J Lipid Res 1999;40:345-353.
Fatty Acyl Moiety in ? Position
% Occurrence
Subbaiah PV et al. Biochim Biophys Acta 1989;1003:145-150.
Phosphatidylcholine Composition of Human HDL
PO = 1-palmitoyl-2-oleoyl-; PL = 1-palmitoyl-2-linoleoyl-; PA = 1-palmitoyl-2-arachidonyl-
Fatty Acyl Moiety in ? Position
16:0
18:0
18:1
18:2
POPC, PLPC and PAPC account for 55% of all PC molecular species
PO
PL
PA
VCAM-1 Expression (% of 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
POPC
0
2
4
6
8
PAPC
PLPC
rHDL Particle Molarity (mM)
PL = 1-palmitoyl-2-linoleoyl-; PA = 1-palmitoyl-2-arachidonyl-; PO = 1-palmitoyl-2-oleoyl-; rHDL = reconstituted HDL
Additional Anti-inflammatory Properties of HDL
HDL bind and neutralize proinflammatory lipopolysaccharides
The acute phase reactant SAA binds to plasma HDL, which possibly neutralizes the effects of SAA
Baumberger C et al. Pathobiology 1991;59:378-383; Benditt EP et al. Proc Natl Acad Sci U S A 1977;74:4025-4028.
Animal Studies
Increasing the concentration of LDL or remnant particles in animal models results in expression of endothelial cell adhesion molecules at the sites where atherosclerotic lesions develop
Infusion or overexpression of apoA-I in animal models reduces oxidation of LDL and reduces endothelial cell adhesion molecule expression
Sakai A et al. Arterioscler Thromb Vasc Biol 1997;17:310-316; Dimayuga P et al. Biochem Biophys Res Commun 1999;264:465-468; Cockeril