Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1518-1525
© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Monocyte Chemoattractant Protein-1 Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice
From the Departments of Metabolic Disease (R.J.A., P.-A.K.B., S.L., W.W.), Molecular Sciences (P.M.M.), and Animal Health (E.N.), Central Research Division, Pfizer Inc, Groton, Conn; and Dana-Farber Cancer Institute (B.J.R.), Harvard Medical School, Boston, Mass.
Correspondence to Dr Robert J. Aiello, Pfizer Inc, Central Research, Eastern Point Road, Groton, CT 06340. E-mail robert_j_aiello{at}groton.pfizer.com
Abstract—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 (P<0.001) 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.
Key Words: bone marrow • CD11b • F4/80 • oxidized lipid • chemokines
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S. Reddy, S. Hama, V. Grijalva, K. Hassan, R. Mottahedeh, G. Hough, D. J. Wadleigh, M. Navab, and A. M. Fogelman Mitogen-activated Protein Kinase Phosphatase 1 Activity Is Necessary for Oxidized Phospholipids to Induce Monocyte Chemotactic Activity in Human Aortic Endothelial Cells J. Biol. Chem., May 11, 2001; 276(20): 17030 - 17035. [Abstract] [Full Text] [PDF]
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M. Roque, W. J.H. Kim, M. Gazdoin, A. Malik, E. D. Reis, J. T. Fallon, J. J. Badimon, I. F. Charo, and M. B. Taubman CCR2 Deficiency Decreases Intimal Hyperplasia After Arterial Injury Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 554 - 559. [Abstract] [Full Text] [PDF]
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M. K. Froberg, A. Adams, N. Seacotte, J. Parker-Thornburg, and P. Kolattukudy Cytomegalovirus Infection Accelerates Inflammation in Vascular Tissue Overexpressing Monocyte Chemoattractant Protein-1 Circ. Res., December 7, 2001; 89(12): 1224 - 1230. [Abstract] [Full Text] [PDF]
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