CCL2 MCP1 and CCR2

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Recruitment of mononuclear leukocytes to the atherosclerotic lesion is a critical step in both the initial development and further progression of the plaque. Monocyte chemoattractant protein (MCP)-1, CCL2, is a member of the CC chemokine family and is a potent monocyte and lymphocyte chemoattrac-tant (22). It is produced by various cell types in the arterial wall including endothelial cells (23,24), smooth muscle cells (25), and fibroblasts (23). CCL2 initiates signal transduction through binding to CC chemokine receptor 2 (CCR2), its only known receptor, which is highly expressed on macrophages and T lymphocytes (Fig. 2). There is a significant amount of literature supporting a major role for this chemokine-receptor pair in the pathogenesis of atherosclerosis (AS).

Increased CCL2 has been detected in macrophage-rich human atherosclerotic lesions (26) and in the blood of patients with acute coronary syndrome (implying an unstable plaque) (27,28). It is found in the arteries of primates on a high-cholesterol diet (29) and is upregulated in vascular endothelial cells and

Chemokine Receptor Ccr2 Responses

Fig. 2. The role of MCP-1 (CCL2)/CCR2 in atherosclerosis is thought to occur through the response of endothelial cells and vascular smooth muscle cells to oxidized lipoproteins. After injury by oxidized lipoproteins, MCP-1 is released and attracts CCR2-expressing monocytes to the site of injury and activates them to secrete inflammatory mediators.

Fig. 2. The role of MCP-1 (CCL2)/CCR2 in atherosclerosis is thought to occur through the response of endothelial cells and vascular smooth muscle cells to oxidized lipoproteins. After injury by oxidized lipoproteins, MCP-1 is released and attracts CCR2-expressing monocytes to the site of injury and activates them to secrete inflammatory mediators.

smooth muscle cells exposed to minimally modified lipids (30). Localization to the lesion, expression by cell types within the plaque, and upregulation in the setting of traditional atherosclerotic risk factors suggests that CCL2 expression plays a role in the development of AS. CCR2 expression has been found to be increased by 2.4-fold in monocytes isolated from hypercholesterolemic patients (31). These monocytes exhibited increased chemotactic responses to CCL2. These studies suggest a possible mechanistic link between hyperlipid-emia, foam cell formation, and atherosclerosis progression.

The roles of CCL2 in AS have been extensively evaluated using AS-susceptible mice with either over- or underexpression of CCL2. Aiello et al. (32) demonstrated by bone marrow transplantation studies that CCL2 overexpression in bone marrow-derived cells results in increased lipid accumulation, increased oxidized lipids, and increased macrophage markers relative to control mice at 20 weeks. CCL2 deficiency in LDLR-/- mice on a high-cholesterol diet for 12 to 14 weeks resulted in a 79% decrease in atherosclerotic lesion area at the aortic root and a similar decrease in the lesions in the thoracic and abdominal aorta (33). CCL2 deficiency in apo B-transgenic mice fed a high-fat diet for 15 to 18 weeks resulted in a 60% to 70% decrease in aortic root lesion size (34).

The findings with CCR2-deficient mice have been largely similar to that for CCL2. CCR2-/-, Apo E-/- mice fed a high-fat diet had a significant decrease in macrophage infiltration of the aortic sinus at 5 weeks, decreased lesion area at the aortic root at 5, 9, and 13 weeks, and decreased thoracic/abdominal aortic lesion area at 13 weeks compared with Apo E-/- controls (35). These reductions occurred despite similar cholesterol profiles in both groups of animals. When fed a normal chow diet, CCR2-/-, Apo E-/- mice had one-third smaller aortic sinus lesions at 4 months compared with CCR2+/-, Apo E-/- littermates (36). CCR2 deficiency did not alter the peripheral blood cholesterol profile (35,36). In the femoral arterial injury model, CCR2 deficiency resulted in a 61% reduction in intimal area and a 62% reduction in the intima:media ratio (37). Five days after injury, the medial proliferation index, as determined by bromode-oxyuridine incorporation, was decreased by 60% in CCR2-/- mice (37), a finding similar to that seen with CCL2-deficient mice (38). These results demonstrate that CCL2/CCR2 plays an important role in mediating intimal hyperplasia and smooth muscle cell proliferation. In particular, CCL2/CCR2 may be an important target for inhibiting the response to acute arterial injury such as occurs after angioplasty, thus ameliorating the complication of restenosis. This would be particularly important in light of the results of a study of patients with restenosis after coronary angioplasty who were shown to have elevated levels of plasma CCL2 (39).

Genetic data also support a role for CCR2 in atherosclerosis. The human CCR2 gene has a single nucleotide polymorphism (SNP) that results in a Val to Ile substitution at position 64 (V64I) (40) that is associated with decreased CCR2 function (41-43). The CCR2 I64 isoform is associated with a decrease in the extent of coronary artery calcification (CAC) in a manner that is independent of traditional cardiovascular disease risk factors (44). These data provide the final link suggesting that CCL2/CCR2 plays a role in AS in animal models and that it may play an important role in human disease.

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