Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein graft neointimal formation

Abstract

Clinical outcome of vascular bypass surgery using autologous vein graft is limited by neointimal formation associated with vein graft failure. Because inflammatory changes are one of the main pathologic features of vein graft failure, monocyte chemoattractant protein-1 (MCP-1) might therefore underlie in the mechanism of vein graft failure. There is no direct evidence, however, that shows the benefits of local anti-MCP-1 therapy as a novel molecular approach for prevention of vein graft failure. To block MCP-1, we used an N-terminal deletion mutant of the MCP-1 gene (7ND), which lacks the N-terminal amino acids 2 to 8, binds to its receptor CCR2, and blocks MCP-1-mediated monocyte chemotaxis. 7ND works as dominant-negative inhibitor of MCP-1. Autologous canine jugular vein grafts were transfected by incubating them ex vivo in a solution with or without adenovirus vectors containing 7ND gene or LacZ gene, and interposed into the carotid arteries. Adenovirus-mediated gene transfer of 7ND, but not LacZ gene transfer, significantly attenuated inflammation (monocyte infiltration per mm2 on day 7: 328+/-59, 220+/-11, 26+/-4 in control, LacZ, and 7ND groups, respectively, P<.05, n=4 each) and proliferation (appearance of proliferating cells per mm2 on day 7: 1005+/-186, 756+/-106, 252+/-27 in control, LacZ, and 7ND groups, P<.05, n=4 each) at 7 days after the operation and thus suppressed neointimal formation (neointimal area in mm2 on day 28: 1.63+/-0.51, 1.96+/-0.48, 0.68+/-0.10 in control, LacZ, and 7ND groups, P<.05, n=4 each). This strategy also attenuated upregulation of MCP-1 activities but did not affect endothelial regeneration process. Blockade of MCP-1 by adenoviral gene transfer of 7ND limits neointimal formation associated with vein graft failure in dogs. This study highlights the potential therapeutic benefit of local anti-MCP-1 therapy for prevention of neointimal formation associated with vein graft failure.