(Circulation. 2001;103:2096.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
New Anti–Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Atherosclerosis in Apolipoprotein E–Knockout Mice
From the Department of Cardiovascular Medicine (W.N., K.E., S.K., C.K., M.K., S.I., A.T.), Graduate School of Medical Sciences, and the Laboratory of Nutrition Chemistry (K.I.), Division of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan; and New Product Research Laboratories (C.A., K.N.), Daiichi Pharmaceutical Co, Tokyo, Japan.
Correspondence to Kensuke Egashira, MD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp
Background—Monocyte recruitment into the arterial wall and its activation may be the central event in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for monocyte recruitment, and its receptor (CCR2) may mediate such in vivo response. Although the importance of the MCP-1/CCR2 pathway in atherogenesis has been clarified, it remains unanswered whether postnatal blockade of the MCP-1 signals could be a unique site-specific gene therapy.
Methods and Results—We devised a new strategy for anti–MCP-1 gene therapy to treat atherosclerosis by transfecting an N-terminal deletion mutant of the human MCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E–knockout mice. This strategy effectively blocked MCP-1 activity and inhibited the formation of atherosclerotic lesions but had no effect on serum lipid concentrations. Furthermore, this strategy increased the lesional extracellular matrix content.
Conclusions—We conclude that this anti–MCP-1 gene therapy may serve not only to reduce atherogenesis but also to stabilize vulnerable atheromatous plaques. This strategy may be a useful and feasible form of gene therapy against atherosclerosis in humans.
Key Words: apolipoproteins • atherosclerosis • gene therapy
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