Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury
Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury
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DOI：
10.1161/01.cir.99.24.3199
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发表时间：
1999-06-22
期刊：
影响因子：
37.8
通讯作者：
McEwan, JR
中科院分区：
文献类型：
--
作者：
Dollery, CM;Humphries, SE;McEwan, JR
背景-细胞迁移是损伤引起的新内膜增生的主要因素，并且取决于动脉壁内蛋白水解平衡向基质分解的改变。这部分是由基质金属蛋白酶 (MMP) 及其天然抑制剂、金属蛋白酶组织抑制剂 (TIMP) 介导的。 方法和结果 - 用 Av1 感染大鼠平滑肌细胞 (SMC) 后，体外观察到生物活性和免疫反应性 TIMP-1 表达增加。TIMP1（一种含有人 TLMP1 cDNA 的腺病毒载体），用 Av1 感染大鼠 SMC。与对照病毒感染细胞相比，Av1.TIMP1 体外迁移减少了 27%（每高倍视野 37.6 +/- 4.34 与 51 +/- 5.01 个细胞，P < 0.05），将腺病毒载体递送至受损大鼠颈动脉，4 天后，鉴定出免疫反应蛋白，SMC 迁移减少 60%（5.2 +/- 0.5 与每切片 12.8 +/- 1.5 个细胞，P < 0.05，n = 5)，受伤后 14 天，接受 Av1.TIMP1 病毒的动物与对照组相比，新内膜面积减少 30%（0.09 +/- 0.01 与 0.14 +/- 0.01 mm(2)，P = 0.02，n = 14），结论-对动脉球囊的反应损伤涉及 MMP 依赖性 SMC 迁移，并且可以通过腺病毒基因转移跨壁表达 TIMP-1 在体内减弱。
Background-Cell migration is a major contributor to injury-induced neointimal hyperplasia and depends on alteration of the proteolytic balance within the arterial wall toward matrix breakdown. This is partly mediated by the matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs).Methods and Results-An increase in expression of biologically active and immunoreactive TIMP-1 was seen in vitro after infection of rat smooth muscle cells (SMCs) with Av1.TIMP1 (an adenoviral vector containing the human TLMP1 cDNA), Infection of rat SMCs with Av1.TIMP1 reduced migration in vitro by 27% compared with control virus-infected cells (37.6 +/- 4.34 versus 51 +/- 5.01 cells per high-power field, P < 0.05), The adenoviral vector was delivered to the injured rat carotid artery, and 4 days later, immunoreactive protein was identified and migration of SMCs reduced by 60% (5.2 +/- 0.5 versus 12.8 +/- 1.5 cells per section, P < 0.05, n = 5), Neointimal area 14 days after injury showed a 30% reduction in the animals receiving the Av1.TIMP1 virus compared with controls (0.09 +/- 0.01 versus 0.14 +/- 0.01 mm(2), P = 0.02, n = 14),Conclusions-The response to arterial balloon injury involves MMP-dependent SMC migration and can be attenuated in vivo by the transmural expression of TIMP-1 by adenoviral gene transfer.