Circulation Research. 2004;94:253-261
Published online before print December 1, 2003, doi: 10.1161/01.RES.0000109793.17591.4E
Published online before print December 1, 2003, doi: 10.1161/01.RES.0000109793.17591.4E
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Antagonism of RANTES Receptors Reduces Atherosclerotic Plaque Formation in Mice
From the Division of Cardiology (N.R.V., B.K., G.P., F. Mulhaupt, F. Mach), Foundation for Medical Research; Endocrinology and Diabetes Division (R.W.J.), Faculty of Medicine, University Hospital Geneva; and Serono Pharmaceutical Research Institute (A.E.I.P.), Geneva, Switzerland.
Correspondence to François Mach, MD, Cardiology Division, Department of Medicine, University Hospital Geneva, Foundation for Medical Research, 64 Ave Roseraie, 1211 Geneva 4, Switzerland. E-mail Francois.Mach{at}medecine.unige.ch
Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a chemokine pathway in vivo with the CC chemokine antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major chemokines and chemokine receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC chemokine or its receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a chemokine receptor antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease.
Key Words: atherogenesis • leukocytes • vascular cells • chemokines • chemokine receptor antagonists
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