The Role of MCP-1 in Atherosclerosis

Chemokines are involved in the pathogenesis of atherosclerosis by promoting directed migration of inflammatory cells. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, has been detected in atherosclerotic lesions by anti-MCP-1 antibody detection1 and in situ hybridization.2-3 MCP-1 mRNA expression has been detected in endothelial cells, macrophages and vascular smooth muscle cells in atherosclerotic arteries of patients undergoing bypass revascularization.4 MCP-1 functions in the development of atherosclerosis by recruiting monocytes into the subendothelial cell layer (for reviews, see ref. 5 and 6).

Figure 1. MCP-1 released by smooth muscle and endothelial cells promotes the recruitment of monocytes and macrophages to the subendothelial cell layer. Deposition of lipids within these monocytes and macrophages then leads to development of atherosclerotic lesions.

MCP-1 is critical for the initiation and development of atherosclerotic lesions. During the progression of atherosclerosis, there is an accumulation of low-density lipoprotein (LDL) within macrophages and monocytes present in the intimal layer. Deposition of lipids within these cells leads to the formation and eventual enlargement of atherosclerotic lesions. Gu, et al.7 fed a high cholesterol diet to mice deficient in LDL that also expressed either wild type MCP-1 or were MCP-1-deficient. The LDL/MCP-1-deficient mice deposited less lipids and had fewer macrophages present within their aortic walls. In a similar study, Boring, et al.8 noted an overall decrease in atherosclerotic lesion size in mice deficient for the MCP-1 receptor, CCR-2. Significantly fewer macrophages and monocytes were present in the aortas of CCR-2-deficient mice and the overall plasma cholesterol levels were unaffected by the CCR-2 genotype. Collectively, these two studies suggest a non-cholesterol-mediated effect of MCP-1 in the development of atherosclerotic lesions. MCP-1 plays a crucial role in initiating atherosclerosis by recruiting macrophages and monocytes to the vessel wall. Development of therapeutic drugs for atherosclerosis specifically targeted against MCP-1 and/or its receptor, CCR-2, may prove useful in the prevention of atherosclerotic lesion development.


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