Local overexpression of monocyte chemoattractant protein-1 at vessel wall induces infiltration of macrophages and formation of atherosclerotic lesion: synergism with hypercholesterolemia.
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.
Namiki
Masayuki
M
Division of Cardiovascular and Respiratory Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Kawashima
Seinosuke
S
Yamashita
Tomoya
T
Ozaki
Masanori
M
Hirase
Tetsuaki
T
Ishida
Tatsuro
T
Inoue
Nobutaka
N
Hirata
Ken-ichi
K
Matsukawa
Akihiro
A
Morishita
Ryuichi
R
Kaneda
Yasufumi
Y
Yokoyama
Mitsuhiro
M
D000818:Animals; D000911:Antibodies, Monoclonal; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000209:etiology; D002465:Cell Movement / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000473:pathology*; D006937:Hypercholesterolemia / Q000150:complications; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D008297:Male; D009000:Monocytes / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D014162:Transfection; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol