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Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis

Abstract

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 receptors1,2. 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 plaques3,4, in arteries of primates on a hypercholesterolaemic diet5 and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids5,6. 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 mice8,9,10 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.

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Figure 1: Macrophage infiltration of the aortic sinus in apoE−/− mice fed a high-fat (Western) diet for 5 weeks.
Figure 2: Mean lesion area in the aortic root.
Figure 3: Lesion coverage in the aortas of CCR2+/− and CCR2−/− mice.
Figure 4: Lipoprotein profile of plasma from CCR2+/+ and CCR2−/− mice.

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Acknowledgements

We thank D. Sanan, D. Newland and L. Jensen for help with tissue preparation and staining; D. Dichek for advice on statistical analysis; J. C. W. Carroll, N. C. Shea and S. Gonzales for figurepreparation; J. Ernst for assistance with fluorescent microscopy; G. Howard and S. Ordway for editorial expertise; and A. Chen for manuscript preparation. We also thank R. Pitas, R. Farese and K.Weisgraber for careful readings of the manuscript. This work was supported in part by a grant from the NIH to I.F.C.

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Boring, L., Gosling, J., Cleary, M. et al. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894–897 (1998). https://doi.org/10.1038/29788

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