Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein graft neointimal formation
Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein graft neointimal formation
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DOI：
10.1016/j.jvs.2007.01.066
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发表时间：
2007-06-01
影响因子：
4.3
通讯作者：
Tominaga, Ryuji
中科院分区：
文献类型：
--
作者：
Tatewaki, Hideki;Egashira, Kensuke;Tominaga, Ryuji
背景：使用自体静脉移植物的血管搭桥手术的临床结果受到与静脉移植物失败相关的新生内膜形成的限制。由于炎症改变是静脉移植失败的主要病理特征之一，因此单核细胞趋化蛋白-1(MCP-1)可能是移植静脉失败的机制之一。然而，没有直接的证据表明局部抗MCP-1治疗是预防静脉移植失败的一种新的分子方法。方法：为了阻断MCP-1，我们使用了MCP-1基因的N端缺失突变体(7ND)，它缺乏N端氨基酸2到8，与其受体CCR2结合，阻断了MCP-1介导的单核细胞趋化。7ND是MCP-1的显性负抑制因子。结果：腺病毒介导的7ND基因转导，而不转导LacZ基因，可显著减轻炎症反应(7d时，对照组、LacZ组、7ND组分别为328+/-59、220+/-11、26+/-4，P<；.05，n=4)和增殖(增殖细胞数/mm(2))：对照组1005+/-186,756+/-106,252+/-27，P
Background: 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.Methods: 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.Results: Adenovirus -mediated gene transfer of 7ND, but not LacZ gene transfer, significantly attenuated inflammation (monocyte infiltration per mm(2) 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 mm(2) on day 7: 1005 +/- 186, 756 +/- 106, 252 +/- 27 in control, LacZ, and 7ND groups, P