Essential role of monocyte chemoattractant protein-1 (MCP1) in development of restenotic changes (neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits

虽然移植自体静脉作为血管替代物治疗外周动脉闭塞性疾病是获得最佳长期效果的手术方法，但晚期静脉移植失败仍然是血管外科医生面临的一个重大问题。单核细胞趋化蛋白-1 （MCP-1）介导的动脉壁单核细胞的浸润和活化可能是血管成形术后再狭窄的主要原因。然而，没有直接证据支持MCP-1在再狭窄发展中的明确作用。我们最近设计了一种通过转染n端缺失来抗mcp -1基因治疗的新策略。MCP-1基因突变进入骨骼肌。我们发现球囊损伤后，MCP-1 mRNA水平早在第1天就显著升高，但随着时间的推移而下降；然而，在所有时间点，MCP-1在损伤动脉中的基因表达在第3、7和28天显著高于未损伤的对照动脉。ram11阳性巨噬细胞在第1天表现不明显，但在第3、7、28天表现明显。我们发现7ND基因转染明显抑制球囊损伤后巨噬细胞向内膜、中膜和外膜的浸润。我们发现7ND组的内膜面积和内膜/中膜比小于PBS或空质粒组，负重构（更小的管腔大小、IEL和EEL）在7ND组比PBS或空质粒组少。由于抑制了新生内膜的形成和负重构，管腔狭窄被阻止了。mcp -1介导的单核细胞浸润在高胆固醇血症家兔球囊损伤再狭窄改变的发展中是必要的。这种策略可能是一种有用的、实用的基因治疗人类再狭窄的形式。

Although grafting with an autologous vein as a vascular substitute in the treatment of peripheral arterial occlusive disease is the surgical procedure that yields the best long-term results, late vein graft failure remains a significant problem for vascular surgeons. Infiltration and activation of monocytes in, the arterial wall mediated by monocyte chemoattractant protein-1 (MCP-1) might be a major cause of restenosis after angioplasty. However, there is no direct evidence to support a definite role of MCP-1 in the development of restenosis.We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion. mutant of the MCP-1 gene into skeletal muscles.We found that after balloon injury, the MCP-1 mRNA level significantly increased as early as day 1, but declined with time ; at all points in time, however, gene expression of MCP-1 in the injured artery was significantly higher on days 3, 7, and 28 than that in the noninjured control artery. Appearance of RAM11-positive macrophages were not distinct on day 1, but became evident on days 3, 7, and 28. We found that 7ND gene transfer markedly suppressed macrophage infiltration into the intima, media, and adventitia after balloon injury.We found that intimal area and intima/media ratio were less in 7ND group than in PBS or empty plasmid group and that negative remodeling (smaller lumen size, IEL and EEL) was less in 7ND group than in PBS or empty plasmid group. As a result of the inhibition of neointimal formation and negative remodeling, luminal narrowing was prevented.MCP-1-mediated monocyte infiltration is necessary in the development of restenotic changes to balloon injury in hypercholesterolemic rabbits. This strategy may be a useful and practical form of gene therapy against human restenosis.