Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Expression in Endothelial Cells

Monocyte

Vessel Lumen

Adhesion Molecules

LDL
MCP-1
Endothelium

LDL

Cytokines

Modified LDL

Macrophage

Intima

Nathan CF. J Clin Invest 1987;79:319-326.

Inhibition of Adhesion Molecules

Monocyte

HDL Inhibit Adhesion Molecule Expression

LDL Vessel Lumen

Adhesion Molecules Cytokines

MCP-1

Endothelium

LDL

Modified LDL
Foam Cell

HDL Inhibit Oxidation of LDL

Macrophage

HDL Promote Cholesterol Efflux

Intima

Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

Recruitment of Blood Monocytes by Endothelial Cell Adhesion Molecules

Monocyte

Rolling

Sticking

Vessel Lumen

Transmigration
ESelectin VCAM-1 ICAM-1
Endothelium

MCP-1

Intima
Charo IF. Curr Opin Lipidol 1992;3:335-343.

Heterogeneity of HDL
Particle Shape Discoidal Apolipoprotein Composition

Spherical

A-I HDL

A-I/A-II HDL

A-II HDL

Particle Size

Lipid Composition TG, CE, and PL

HDL2b HDL2a HDL3a HDL3b HDL3c

Rye KA et al. Atherosclerosis 1999;145:227-238.

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.

Atherosclerosis is an Inflammatory Disease

Monocyte

Vessel Lumen

Endothelium

Cytokines
Growth Factors Metalloproteinases

Cell Proliferation Matrix Degradation

Foam Cell

Macrophage

Intima

Ross R. N Engl J Med 1999;340:115-126.

Modified LDL Stimulate Expression of MCP-1 in Endothelial Cells

Monocyte

Vessel Lumen

LDL
Endothelium

MCP-1 LDL

Modified LDL
Intima
Navab M et al. J Clin Invest 1991;88:2039-2046.

Differentiation of Monocytes into Macrophages

Monocyte

Vessel Lumen

LDL
MCP-1
Endothelium

LDL
Intima

Modified LDL
Modified LDL Promote Differentiation of Monocytes into Macrophages

Macrophage

Steinberg D et al. N Engl J Med 1989;320:915-924.

Macrophages Express Receptors That Take up Modified LDL

Monocyte

Vessel Lumen

Adhesion Molecules

LDL
MCP-1
Endothelium

LDL

Modified LDL Taken up by Macrophage

Foam Cell Macrophage

Intima

Steinberg D et al. N Engl J Med 1989;320:915-924.

Macrophages and Foam Cells Express Growth Factors and Proteinases

Monocyte

Vessel Lumen

LDL
Adhesion Molecules

MCP-1

LDL

Endothelium

Cytokines

Modified LDL

Intima
Growth Factors Metalloproteinases

Macrophage

Foam Cell

Cell Proliferation Matrix Degradation

Ross R. N Engl J Med 1999;340:115-126.

Structure of HDL
apoA-I

Surface Monolayer of Phospholipids and Free Cholesterol

apoA-II

Hydrophobic Core of Triglyceride and Cholesteryl Esters

Rye KA et al. Atherosclerosis 1999;145:227-238.

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.

Role of LDL in Inflammation

LDL Readily Enter the Artery Wall Where They May be Modified

Vessel Lumen

LDL

Endothelium

Oxidation of Lipids and ApoB Aggregation

LDL

Hydrolysis of Phosphatidylcholine to Lysophosphatidylcholine

Other Chemical Modifications

Modified LDL
Modified LDL are Proinflammatory
Steinberg D et al. N Engl J Med 1989;320:915-924.

Intima

Structure of HDL Particle

A-I A-I

CE
TG

A-II
A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides

Production of HDL by Liver and Intestine

Liver Intestine

A-I

A-I

A-II HDL
A-I, A-II = apolipoprotein A-I, A-II

HDL

HDL Metabolism and Reverse Cholesterol Transport

Bile A-I
F C

A-I

CE

SR-BI Liver

CE

LCAT

Mature HDL

Nascent HDL

F C

ABC1

FC

CE

Macrophage

ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger receptor class BI

Role of CETP in HDL Metabolism

Bile
F C

Mature HDL A-I

CE

Nascent HDL A-I

LCAT
F C

Macrophage CE

CE

SR-BI Liver LDLR

CETP CE VLDL/LDL B

FC ABC1 SRA

CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein

Role of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolism

Endothelium LP L A-I
PL CE
TG

B TG CM/VLDL

C-II

B
CMR/IDL

A-I
PL

HL

HDL2

CE Kidney

HDL3

CM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein; HL = hepatic lipase; IDL = intermediate-density lipoprotein; LPL = lipoprotein lipase; PL = phospholipase; TG = triglyceride

Lipoprotein Classes and Inflammation

Chylomicrons, VLDL, and their catabolic remnants

LDL

HDL

> 30 nm

2022 nm

915 nm
Potentially antiinflammatory

Potentially proinflammatory

Structure of LDL
Surface Monolayer of Phospholipids and Free Cholesterol

apoB
Hydrophobic Core of Triglyceride and Cholesteryl Esters
Murphy HC et al. Biochemistry 2000;39:9763-970.

Reverse Cholesterol Transport

Normal Endothelium