Anti–Monocyte Chemoattractant Protein-1/Monocyte Chemotactic and Activating Factor Antibody Inhibits Neointimal Hyperplasia in Injured Rat Carotid Arteries

Abstract

Abstract-Monocyte chemoattractant protein-1 (MCP-1)/monocyte chemotactic and activating factor (MCAF) has been suggested to promote atherogenesis. The effects of in vivo neutralization of MCP-1 in a rat model were examined in an effort to clarify the role of MCP-1 in the development of neointimal hyperplasia. Competitive polymerase chain reaction analysis revealed maximum MCP-1 mRNA expression at 4 hours after carotid arterial injury. Increased immunoreactivities of MCP-1 were also detected at 2 and 8 hours after injury. Either anti-MCP-1 antibody or nonimmunized goat IgG (10 mg/kg) was then administered every 12 hours to rats that had undergone carotid arterial injury. Treatment with 3 consecutive doses of anti-MCP-1 antibody within 24 hours (experiment 1) and every 12 hours for 5 days (experiment 2) significantly inhibited neointimal hyperplasia at day 14, resulting in a 27.8% reduction of the mean intima/media ratio (PϽ0.05) in experiment 1 and a 43.6% reduction (PϽ0.01) in experiment 2. This effect was still apparent at day 56 (55.6% inhibition; PϽ0.05). The number of vascular smooth muscle cells in the neointima at day 4 was significantly reduced by anti-MCP-1 treatment, demonstrating the important role of MCP-1 in early neointimal lesion formation. However, recombinant MCP-1 did not stimulate chemotaxis of vascular smooth muscle cells in an in vitro migration assay. These results suggest that MCP-1 promotes neointimal hyperplasia in early neointimal lesion formation and that neutralization of MCP-1 before, and immediately after, arterial injury may be effective in preventing restenosis after angioplasty. Further studies are needed to clarify the mechanism underlying the promotion of neointimal hyperplasia by MCP-1. (Circ Res. 1999;84:306-314.)Key Words: monocyte chemoattractant protein-1/monocyte chemotactic and activating factor Ⅲ angioplasty Ⅲ restenosis Ⅲ macrophage Ⅲ smooth muscle cell L ate restenosis after balloon angioplasty remains the most limiting factor with regard to the long-term effectiveness of the procedure, and it is partially attributed to neointimal hyperplasia. 1,2 Despite some success of various treatments [3][4][5] in reducing neointimal hyperplasia in animal models, no sufficiently effective therapy has been confirmed in clinical trials. In the development of neointima, several cell types, such as monocytes/macrophages, vascular smooth muscle cells (VSMCs), and T lymphocytes, play diverse roles. Growth factors and cytokines mediate the interactions among these cells. 6,7 One of these soluble factors, monocyte chemoattractant protein-1 (MCP-1)/monocyte chemotactic and activating factor (MCAF), has been reported to be expressed early in the injured arterial wall. 8 MCP-1 is a potent chemotactic factor of monocytes 9,10 and is produced by activated endothelial cells 11 and VSMCs. 12 It has also been detected in human atheromatous plaques using immunohistochemical staining and in situ hybridization. 13 Monocytes/macrophages recruited into injured arterial walls become foam cells, the foc...

CCN4 Regulates Vascular Smooth Muscle Cell Migration and Proliferation

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Roles and Relationship of Macrophages and Monocyte Chemotactic and Activating Factor/Monocyte Chemoattractant Protein-1 in the Ischemic and Reperfused Rat Heart

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