Published online before print January 22, 2004, doi: 10.1161/01.ATV.0000118275.60121.2b
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Monocyte Chemoattractant Protein-1 Is an Essential Inflammatory Mediator in Angiotensin II-Induced Progression of Established Atherosclerosis in Hypercholesterolemic Mice
From the Department of Cardiovascular Medicine (W.N., S.K., M.I., M.U., S.I., K.H., Q.Z., A.T., K.E.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and the New Product Research Laboratories (K.N.), Dai-ichi Pharmaceutical Company, Tokyo, Japan.
Correspondence to Dr Kensuke Egashira, 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
Objective— Chronic inflammatory processes might be involved in the progression and destabilization of atherosclerotic plaques. Therefore, identification of the mechanism underlying arterial inflammatory function might lead to the development of novel therapeutic strategies. Angiotensin II (AngII) is implicated in atherogenesis by activating the vascular inflammation system, mainly through monocyte chemotaxis. Therefore, we hypothesized that AngII increases plaque size and promotes destabilization of established atheromas by activating the monocyte chemoattractant protein-1 (MCP-1) pathway.
Methods and Results— We report here that 4-week infusion of AngII not only increased plaque size but also induced a destabilization phenotype (ie, increased macrophages and lipids and decreased collagen and smooth muscle cells) of pre-existing atherosclerotic lesions of hypercholesterolemic mice. AngII also enhanced the gene expression of inflammatory cytokines (TNF
, IL-6, etc.) and chemokines (MCP-1, CCR2, etc). Blockade of MCP-1, by transfecting the deletion mutant of the human MCP-1 gene into the skeletal muscles, limited AngII-induced progression and destabilization of established atherosclerotic lesions and suppressed the induction of proinflammatory genes.
Conclusions— These data suggest that MCP-1 functions as a central inflammatory mediator in the AngII-induced progression and changes in plaque composition of established atheroma.
Key Words: atherosclerosis • hypercholesterolemia • cell adhesion molecules • inflammation • gene therapy
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