Published online before print November 30, 2006, doi: 10.1161/01.ATV.0000253886.44609.ae
© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Ccr5 But Not Ccr1 Deficiency Reduces Development of Diet-Induced Atherosclerosis in Mice
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
This article has been cited by other articles:
 |
|
 |
|
  V. Z. Rocha, E. J. Folco, G. Sukhova, K. Shimizu, I. Gotsman, A. H. Vernon, and P. Libby Interferon-{gamma}, a Th1 Cytokine, Regulates Fat Inflammation: A Role for Adaptive Immunity in Obesity Circ. Res., August 29, 2008; 103(5): 467 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Afzal, S. Kiechl, Y. P. Daryani, A. Weerasinghe, Y. Zhang, M. Reindl, A. Mayr, S. Weger, Q. Xu, and J. Willeit Common CCR5-del32 Frameshift Mutation Associated With Serum Levels of Inflammatory Markers and Cardiovascular Disease Risk in the Bruneck Population Stroke, July 1, 2008; 39(7): 1972 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Braunersreuther, S. Steffens, C. Arnaud, G. Pelli, F. Burger, A. Proudfoot, and F. Mach A Novel RANTES Antagonist Prevents Progression of Established Atherosclerotic Lesions in Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1090 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fougerat, S. Gayral, P. Gourdy, A. Schambourg, T. Ruckle, M. K. Schwarz, C. Rommel, E. Hirsch, J.-F. Arnal, J.-P. Salles, et al. Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-{gamma} Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes Circulation, March 11, 2008; 117(10): 1310 - 1317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J.A. van Wanrooij, S. C.A. de Jager, T. van Es, P. de Vos, H. L. Birch, D. A. Owen, R. J. Watson, E. A.L. Biessen, G. A. Chapman, T. J.C. van Berkel, et al. CXCR3 Antagonist NBI-74330 Attenuates Atherosclerotic Plaque Formation in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 251 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zernecke, I. Bot, Y. Djalali-Talab, E. Shagdarsuren, K. Bidzhekov, S. Meiler, R. Krohn, A. Schober, M. Sperandio, O. Soehnlein, et al. Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis Circ. Res., February 1, 2008; 102(2): 209 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Shagdarsuren, K. Bidzhekov, Y. Djalali-Talab, E. A. Liehn, M. Hristov, R. A. Matthijsen, W. A. Buurman, A. Zernecke, and C. Weber C1-Esterase Inhibitor Protects Against Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice Circulation, January 1, 2008; 117(1): 70 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Krohn, U. Raffetseder, I. Bot, A. Zernecke, E. Shagdarsuren, E. A. Liehn, P. J. van Santbrink, P. J. Nelson, E. A. Biessen, P. R. Mertens, et al. Y-Box Binding Protein-1 Controls CC Chemokine Ligand-5 (CCL5) Expression in Smooth Muscle Cells and Contributes to Neointima Formation in Atherosclerosis-Prone Mice Circulation, October 16, 2007; 116(16): 1812 - 1820. [Abstract] [Full Text] [PDF]
|
|