Circulation. 2003;107:1009-1016
Published online before print February 10, 2003, doi: 10.1161/01.CIR.0000057548.68243.42
Published online before print February 10, 2003, doi: 10.1161/01.CIR.0000057548.68243.42
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(Circulation. 2003;107:1009.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Decreased Atherosclerotic Lesion Formation in CX3CR1/Apolipoprotein E Double Knockout Mice
From Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md (C.C., J.-L.G., P.M.M.); Institut National de la Santé et de la Recherche Médicale, INSERM U543, Laboratoire d’Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris, France (C.C., S.C., P.D.); INSERM U541, Institut Fédératif de Recherche "Circulation Paris VII," Hôpital Lariboisière, Paris, France (S.P., B.E., A.T., Z.M.); and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Md (E.J.L.).
Correspondence to Ziad Mallat, MD, PhD, INSERM U541, Hôpital Lariboisière, 41 Bd de la chapelle, 75010 Paris, France (e-mail ziad.mallat{at}larib.inserm.fr) or Philip M. Murphy, MD, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 10, Room 11N113, Bethesda, MD 20892 (e-mail pmm@nih.gov).
Background— Fractalkine (CX3CL1), a CX3C chemokine, is expressed in the vessel wall and mediates the firm adhesion and chemotaxis of leukocytes expressing its receptor, CX3CR1. A polymorphism in the CX3CR1 gene is associated with low CX3CR1 expression and reduced risk of acute coronary disease in humans.
Methods and Results— We generated CX3CR1-deficient mice (CX3CR1-/-) by targeted gene disruption and crossed them with the proatherogenic apolipoprotein E-deficient mice (apoE-/-). Here we show that the extent of lipid-stained lesions in the thoracic aorta was reduced by 59% in CX3CR1/apoE double knockout mice compared with their CX3CR1+/+/apoE-/- littermates. The development of atherosclerosis in the aortic sinus was also markedly altered in the double knockout mice, with 50% reduction in macrophage accumulation. Although lesions of CX3CR1-/- mice were smaller in size, they retained a substantial accumulation of smooth muscle cells and collagen, features consistent with a stable plaque phenotype. Finally, CX3CR1+/-/apoE-/- mice showed the same reduction in atherosclerosis as the CX3CR1-/-/apoE-/- mice.
Conclusions— The CX3CR1-CX3CL1 pathway seems to play a direct and critical role in monocyte recruitment and atherosclerotic lesion development in a mouse model of human atherosclerosis.
Key Words: atherosclerosis • leukocytes • receptors • inflammation
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C. A. Bursill, R. P. Choudhury, Z. Ali, D. R. Greaves, and K. M. Channon Broad-Spectrum CC-Chemokine Blockade by Gene Transfer Inhibits Macrophage Recruitment and Atherosclerotic Plaque Formation in Apolipoprotein E-Knockout Mice Circulation, October 19, 2004; 110(16): 2460 - 2466. [Abstract] [Full Text] [PDF]
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K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]
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M. Daoudi, E. Lavergne, A. Garin, N. Tarantino, P. Debre, F. Pincet, C. Combadiere, and P. Deterre Enhanced Adhesive Capacities of the Naturally Occurring Ile249-Met280 Variant of the Chemokine Receptor CX3CR1 J. Biol. Chem., May 7, 2004; 279(19): 19649 - 19657. [Abstract] [Full Text] [PDF]
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K. Subbarao, V. R. Jala, S. Mathis, J. Suttles, W. Zacharias, J. Ahamed, H. Ali, M. T. Tseng, and B. Haribabu Role of Leukotriene B4 Receptors in the Development of Atherosclerosis: Potential Mechanisms Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 369 - 375. [Abstract] [Full Text]
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A. Schafer, C. Schulz, M. Eigenthaler, D. Fraccarollo, A. Kobsar, M. Gawaz, G. Ertl, U. Walter, and J. Bauersachs Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion Blood, January 15, 2004; 103(2): 407 - 412. [Abstract] [Full Text] [PDF]
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H. Umehara, E. T. Bloom, T. Okazaki, Y. Nagano, O. Yoshie, and T. Imai Fractalkine in Vascular Biology: From Basic Research to Clinical Disease Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 34 - 40. [Abstract] [Full Text] [PDF]
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E. Lutgens, R.-J. van Suylen, B. C. Faber, M. J. Gijbels, P. M. Eurlings, A.-P. Bijnens, K. B. Cleutjens, S. Heeneman, and M. J.A.P. Daemen Atherosclerotic Plaque Rupture: Local or Systemic Process? Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2123 - 2130. [Abstract] [Full Text] [PDF]
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A. D. Lucas, C. Bursill, T. J. Guzik, J. Sadowski, K. M. Channon, and D. R. Greaves Smooth Muscle Cells in Human Atherosclerotic Plaques Express the Fractalkine Receptor CX3CR1 and Undergo Chemotaxis to the CX3C Chemokine Fractalkine (CX3CL1) Circulation, November 18, 2003; 108(20): 2498 - 2504. [Abstract] [Full Text] [PDF]
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A. Garin, N. Tarantino, S. Faure, M. Daoudi, C. Lecureuil, A. Bourdais, P. Debre, P. Deterre, and C. Combadiere Two Novel Fully Functional Isoforms of CX3CR1 Are Potent HIV Coreceptors J. Immunol., November 15, 2003; 171(10): 5305 - 5312. [Abstract] [Full Text] [PDF]
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 E. Lavergne, B. Combadiere, O. Bonduelle, M. Iga, J.-L. Gao, M. Maho, A. Boissonnas, P. M. Murphy, P. Debre, and C. Combadiere Fractalkine Mediates Natural Killer-Dependent Antitumor Responses in Vivo Cancer Res., November 1, 2003; 63(21): 7468 - 7474. [Abstract] [Full Text] [PDF]
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 P. Ancuta, R. Rao, A. Moses, A. Mehle, S. K. Shaw, F. W. Luscinskas, and D. Gabuzda Fractalkine Preferentially Mediates Arrest and Migration of CD16+ Monocytes J. Exp. Med., June 16, 2003; 197(12): 1701 - 1707. [Abstract] [Full Text] [PDF]
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