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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:373.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Ccr5 But Not Ccr1 Deficiency Reduces Development of Diet-Induced Atherosclerosis in Mice

Vincent Braunersreuther; Alma Zernecke; Claire Arnaud; Elisa A. Liehn; Sabine Steffens; Erdenechimeg Shagdarsuren; Kiril Bidzhekov; Fabienne Burger; Graziano Pelli; Bruno Luckow; François Mach; Christian Weber

From the Division of Cardiology (V.B., C.A., S.S., F.B., G.P., F.M.), Foundation for Medical Research, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland; the Institute for Molecular Cardiovascular Research (IMCAR) (A.Z., E.A.L., E.S., K.B., C.W.), RWTH University Hospital Aachen, Germany; and the Klinikum der Universität München Medizinische Poliklinik–Innenstadt (B.L.), Arbeitsgruppe Klinische Biochemie, München, Germany.

Correspondence to Dr Christian Weber, Institut für Kardiovaskuläre Molekularbiologie, Universitätsklinikum Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail cweber{at}ukaachen.de

Objective— Chemokines and their receptors are crucially involved in the development of atherosclerotic lesions by directing monocyte and T cell recruitment. The CC-chemokine receptors 1 (CCR1) and 5 (CCR5) expressed on these cells bind chemokines implicated in atherosclerosis, namely CCL5/RANTES. Although general blockade of CCL5 receptors reduces atherosclerosis, specific roles of CCR1 and CCR5 have not been unequivocally determined.

Methods and Results— We provide two independent lines of investigation to dissect the effects of Ccr1 and Ccr5 deletion in apolipoprotein E–deficient (ApoE^–/–) mice in a collaboration between Aachen/Germany and Geneva/Switzerland. Different strains of ApoE^–/–Ccr5^–/– mice, ApoE^–/–Ccr1^–/– mice or respective littermates, were fed a high-fat diet for 10 to 12 weeks. Plaque areas were quantified in the aortic roots and thoracoabdominal aortas. Concordantly, both laboratories found that lesion formation was reduced in ApoE^–/–Ccr5^–/– mice. Plaque quality and immune cells were assessed by immunohistochemistry or mRNA analysis. Whereas lesional macrophage content, aortic CD4, and Th1-related Tim3 expression were reduced, smooth muscle cell (SMC) content and expression of interleukin-10 in plaques, lesional SMCs, and splenocytes were elevated. Protection against lesion formation by Ccr5 deficiency was sustained over 22 weeks of high-fat diet or over 26 weeks of chow diet. Conversely, plaque area, T cell, and interferon- content were increased in ApoE^–/–Ccr1^–/– mice.

Conclusion— Genetic deletion of Ccr5 but not Ccr1 in ApoE^–/– mice protects from diet-induced atherosclerosis, associated with a more stable plaque phenotype, reduced mononuclear cell infiltration, Th1-type immune responses, and increased interleukin-10 expression. This corroborates CCR5 as a promising therapeutic target.

Although general blockade of CCL5 receptors reduces atherosclerosis, specific roles of CCR1 and CCR5 have not been unequivocally determined. Genetic deletion of Ccr5 but not Ccr1 in ApoE^–/– mice protects from diet-induced atherosclerosis, resulting in a more stable plaque phenotype with reduced mononuclear cell infiltration and Th1-type immune responses.

Key Words: atherosclerosis • chemokine receptors • inflammation • macrophage • T lymphocyte

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