Circulation. 2002;106:2700-2706
Published online before print October 28, 2002, doi: 10.1161/01.CIR.0000038140.80105.AD
Published online before print October 28, 2002, doi: 10.1161/01.CIR.0000038140.80105.AD
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(Circulation. 2002;106:2700.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Limits Progression and Destabilization of Established Atherosclerosis in Apolipoprotein E–Knockout Mice
From the Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and New Product Research Laboratories (K.N.), Dai-ichi Pharmaceutical Co, Tokyo, Japan.
Correspondence to Kensuke Egashira, MD, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp
Background— Monocyte infiltration into the arterial wall and its activation is the central event in atherogenesis. Thus, monocyte chemoattractant protein-1 (MCP-1) might be a novel therapeutic target against atherogenesis. We and others recently reported that blockade or abrogation of the MCP-1 pathway attenuates the initiation of atheroma formation in hypercholesterolemic mice. It remains unclear, however, whether blockade of MCP-1 can limit progression or destabilization of established lesions.
Methods and Results— We report here that blockade of MCP-1 by transfecting an N-terminal deletion mutant of the MCP-1 gene limited progression of preexisting atherosclerotic lesions in the aortic root in hypercholesterolemic mice. In addition, blockade of MCP-1 changed the lesion composition into a more stable phenotype, ie, containing fewer macrophages and lymphocytes, less lipid, and more smooth muscle cells and collagen. This strategy decreased expression of CD40 and the CD40 ligand in the atherosclerotic plaque and normalized the increased chemokine (RANTES and MCP-1) and cytokine (tumor necrosis factor 
, interleukin-6, interleukin-1ß, and transforming growth factor ß1) gene expression. These data suggest that MCP-1 is a central mediator in the progression and destabilization of established atheroma.
Conclusions— The results of the present study suggest that the inflammatory responses mediated by MCP-1 are important in atherosclerosis and its complications.
Key Words: gene therapy • atherosclerosis • leukocytes • inflammation • lymphocytes
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