Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice.
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.
Aiello
R J
RJ
Department of Metabolic Disease, Central Research Division, Pfizer Inc, Groton, Conn, USA. robert_j_aiello@groton.pfizer.com
Bourassa
P A
PA
Lindsey
S
S
Weng
W
W
Natoli
E
E
Rollins
B J
BJ
Milos
P M
PM
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000209:etiology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000032:analysis; D008264:Macrophages / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis
D001057:Apolipoproteins E; D018932:Chemokine CCL2; D008055:Lipids; D008077:Lipoproteins, LDL; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein