The pro-inflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1), plays a fundamental role in monocyte recruitment and has been implicated as a contributing factor to atherosclerosis. The predominant cell types within the vessel wall-endothelial cells, smooth muscle cells, and macrophages-all contribute to overexpression of MCP-1 in atherosclerotic tissue. In this report we assess the role of MCP-1 expression by leukocytes on lesion progression in a murine model susceptible to atherosclerosis. Bone marrow cells from mice overexpressing a murine MCP-1 transgene on a background of apoE-deficiency or from control mice were transplanted into irradiated apoE-knockout mice. After repopulation of apoE-knockout mice with bone marrow containing the MCP-1 transgene, macrophages expressing the MCP-1 transgene were found in several tissues, including the aorta. Qualitative assessment of atherosclerosis in these mice revealed increased lipid staining, a 3-fold (P0.001) increase in the amount of oxidized lipid, and increased immunostaining for macrophage cell surface markers with anti-F4/80 and anti-CD11b antibodies. There were no differences in plasma lipids, plasma lipoprotein profiles, or body weight between the 2 groups. These results provide the first direct evidence that MCP-1 expression by leukocytes, predominately macrophages, increases the progression of atherosclerosis by increasing both macrophage numbers and oxidized lipid accumulation. (Arterioscler Thromb Vasc Biol. 1999;19:1518-1525.) Key Words: bone marrow CD11b F4/80 oxidized lipid chemokines M onocyte/macrophage cells have an essential role in orchestrating the complex sequence of events involved in the initiation and progression of atherosclerosis. 1 Cells of monocytic origin are present in the developing foam cell lesion, where they engulf lipid and form most of the volume of the fatty streak. 2,3 This early stage of atherosclerosis is characterized by the focal attachment of monocytes to the endothelium and their subsequent transendothelial migration into the vessel wall. 1,4 Once in the tissue, macrophages potentiate the inflammatory response by producing various inflammatory mediators, such as reactive oxygen species and growth factors, including basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta, and other proinflammatory cytokines and chemo-kines. 2,5 Monocytes themselves promote additional monocyte adherence and emigration from the vascular space into sites of inflammation. 6,7 The generation of a murine model in which the apoE gene has been disrupted has provided an important small animal model for the study of atherosclerosis. 8,9 ApoE-deficient mice (apoE-KO) exhibit hypercholesterolemia and develop complex atheromatous lesions similar to those seen in humans. 10,11 These mice develop a full range of lesions, from fatty streaks to raised fibrous plaques, making this model suitable for investigating the pathogenesis of atherosclerosis. To demonstrate the involvement of the macrophage in this pr...
Abstract-The ATP-binding cassette transporter A1 (ABCA1) encodes a membrane protein that promotes cholesterol and phospholipid efflux from cells. Mutations in ABCA1 lead to HDL deficiency and tissue accumulation of macrophages in patients with homozygous Tangier disease. In this study, we examined whether the complete absence of ABCA1 or selected inactivation in macrophages is accompanied by an increase in atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice and LDLR receptor-deficient (LDLr Ϫ/Ϫ ) mice. The absence of ABCA1 led to reduced plasma cholesterol levels in both the apoE Ϫ/Ϫ and LDLr Ϫ/Ϫ mice, along with severe skin xanthomatosis characterized by marked foamy macrophages and cholesterol ester accumulation. However, the complete absence of ABCA1 did not affect the development, progression, or composition of atherosclerotic lesions in either the LDLr Ϫ/Ϫ or the apoE Ϫ/Ϫ mice fed a chow or atherogenic diet. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE Ϫ/Ϫ . Taken together, these findings demonstrate that the complete absence of ABCA1 has a major impact on plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is compensated by a less atherogenic profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels.
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