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

单核细胞趋化蛋白-1 (MCP1) 在高胆固醇血症兔球囊血管成形术后再狭窄变化（新内膜增生和收缩性重塑）发展中的重要作用

基本信息

批准号：
13671241
负责人：
KOMORI Kimihiro
金额：
$ 2.3万
依托单位：
Nagoya University (2002)Kyushu University (2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671241/
关键词：
intimal thickening MCP-1 gene therapy late graft failure 血管内膜肥厚

项目摘要

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.

尽管自体静脉移植作为血管替代物是治疗外周动脉闭塞症的最佳手术方式，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)介导的单核细胞在动脉壁内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在血管再狭窄发生中的确切作用。我们最近设计了一种新的策略，通过导入N端缺失来对抗MCP-1的基因治疗。MCP-1基因在骨骼肌中的突变。我们发现，在球囊损伤后第1天，MCP-1的基因表达水平显著升高，但随着时间的推移而下降；而在所有时间点，损伤动脉中MCP-1的基因表达在第3、7、28天显著高于未损伤的对照动脉。RAM11阳性巨噬细胞的出现在第1天并不明显，但在第3、7和28天变得明显。我们发现7ND基因转移显著抑制了巨噬细胞对球囊损伤后内膜、中膜和外膜的侵袭，7ND组的内膜面积和内膜/中膜比小于PBS组和空质粒组，7ND组的负性重构(小管腔、IEL和EEL)小于PBS组和空质粒组。MCP-1介导的单核细胞浸润在高胆固醇血症兔球囊损伤再狭窄过程中是必要的。这一策略可能是针对人类再狭窄的一种有用和实用的基因治疗形式。