doi: 10.1161/hq0102.102278
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Local Overexpression of Monocyte Chemoattractant Protein-1 at Vessel Wall Induces Infiltration of Macrophages and Formation of Atherosclerotic Lesion
Synergism With Hypercholesterolemia
From the Division of Cardiovascular and Respiratory Medicine (M.N., S.K., T.Y., M.O., T.H., T.I., N.I., K.H., M.Y.), Kobe University Graduate School of Medicine, Kobe, Japan; the Department of Pathology (A.M.), Kumamoto University School of Medicine, Kumamoto, Japan; and the Department of Geriatric Medicine (R.M.) and the Division of Gene Therapy Science (Y.K.), Graduate School of Medicine, Osaka University, Osaka, Japan.
Reprint requests to Seinosuke Kawashima, MD, PhD, Division of Cardiovascular and Respiratory Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail kawashim{at}med.kobe-u.ac.jp
Monocyte/macrophage infiltration to the arterial wall is an initial step in atherosclerosis, and monocyte chemoattractant protein-1 (MCP-1) is thought to play a central role in the recruitment of these cells. In the present study, we examined the role of local expression of MCP-1 at the vessel wall in the initiation and development of atherosclerosis. We transfected the cDNA encoding rat MCP-1 into the vessel wall of the rabbit carotid artery with the use of the hemagglutinating virus of Japan (HVJ)-liposome method. The rabbits were divided into the following groups: (1) those fed normal chow and transfected with MCP-1-HVJ, (2) those fed a high cholesterol diet (1% cholesterol) and transfected with MCP-1-HVJ, and (3) those fed a high cholesterol diet and transfected with control-HVJ. Prescribed diets were started 2 weeks before transfection and were continued for another 2 weeks. In group 1, vascular lesion formation was not found, and anti-rabbit monocyte/macrophage antibody (RAM-11) staining for monocytes/macrophages was negative, although anti-rat MCP-1 antibody (R-17) staining for rat MCP-1 was positive mainly in endothelial cells. Cholesterol feeding increased plasma cholesterol levels to 1801±444 mg/dL in group 2. In group 2, all rabbits displayed neointimal formation with infiltration of RAM-11–positive cells, and a part of the lesion was also positive for Sudan III lipid staining. In group 3, hypercholesterolemia did not induce the infiltration of monocytes/macrophages and subsequent lesion formation in the vessel wall despite definite upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on the endothelium. To initiate atherosclerotic changes, local MCP-1 overexpression at the vessel is not sufficient, and activation of other factors induced by hypercholesterolemia is required.
Key Words: monocyte chemoattractant protein-1 • hypercholesterolemia • atherosclerosis
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