Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis.
Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation and have recently been shown to block the HIV-1 infection of target cells through interactions with chemokine receptors. In addition to their function in viral disease, chemokines have been implicated in the pathogenesis of atherosclerosis. Expression of the CC chemokine monocyte chemoattractant protein-1 (MCP-1) is upregulated in human atherosclerotic plaques, in arteries of primates on a hypercholesterolaemic diet; and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids. To determine whether MCP-1 is causally related to the development of atherosclerosis, we generated mice that lack CCR2, the receptor for MCP-1 (ref. 7), and crossed them with apolipoprotein (apo) E-null mice which develop severe atherosclerosis. Here we show that the selective absence of CCR2 decreases lesion formation markedly in apoE-/- mice but has no effect on plasma lipid or lipoprotein concentrations. These data reveal a role for MCP-1 in the development of early atherosclerotic lesions and suggest that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidaemia and fatty streak formation.
Boring
L
L
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141, USA.
Gosling
J
J
Cleary
M
M
Charo
I F
IF
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000502:physiology; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D018932:Chemokine CCL2 / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000502:physiology; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D008074:Lipoproteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D014280:Triglycerides; D002784:Cholesterol