Monocyte Chemoattractant Protein-1 Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice

Author:

Aiello Robert J.1,Bourassa Patricia-Ann K.1,Lindsey Saralyn1,Weng Weifan1,Natoli Edward1,Rollins Barrett J.1,Milos Patrice M.1

Affiliation:

1. 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.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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