TIMP4 is regulated by vascular injury in rats
TIMP4 is regulated by vascular injury in rats
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DOI：
10.1111/j.1749-6632.1999.tb07777.x
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Shi, YE
中科院分区：
文献类型：
--
作者：
Dollery, CM;McEwan, JR;Shi, YE
- 基底膜降解基质金属蛋白酶（MMPs）在血管损伤后使血管平滑肌细胞迁移中的作用已经在几种动物模型中建立。相比之下，它们的天然抑制剂，基质金属蛋白酶（TIMP）的组织抑制剂的作用，仍然没有得到证实，尽管在其他疾病状态的MMP和TIMP的频繁的共调节。我们通过原位杂交、免疫组化和Western印迹分析研究了球囊损伤后6小时、24小时、3天、7天和14天大鼠颈动脉中TIMP-4的表达和定位的时间过程。TIMP-4蛋白在损伤后24小时开始在损伤的颈动脉外膜表达。在损伤后7天和14天，在整个损伤动脉的新生内膜、中膜和外膜中观察到广泛的TIMP-4免疫染色。Western印迹分析证实TIMP-4蛋白在第7天和第14天的定量增加。原位杂交检测到损伤后24小时TIMP-4表达增加，损伤后7天新生内膜细胞中有明显诱导。然后，我们研究了TIMP-4蛋白对平滑肌细胞在体外通过基质包被的膜迁移的影响，并证明大鼠血管平滑肌细胞的侵袭减少了53%。这些数据和TIMP-4的上调、其积累和胶原沉积的开始之间的时间关系表明TIMP-4在脉管系统的蛋白水解平衡中的重要作用，所述蛋白水解平衡控制受损动脉壁中的平滑肌迁移和胶原积累。
—The role of basement membrane–degrading matrix metalloproteinases (MMPs) in enabling vascular smooth muscle cell migration after vascular injury has been established in several animal models. In contrast, the role of their native inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), has remained unproven despite frequent coregulation of MMPs and TIMPs in other disease states. We have investigated the time course of expression and localization of TIMP-4 in rat carotid arteries 6 hours, 24 hours, 3 days, 7 days, and 14 days after balloon injury by in situ hybridization, immunohistochemistry, and Western blot analysis. TIMP-4 protein was present in the adventitia of injured carotid arteries from 24 hours after injury. At 7 and 14 days after injury, widespread immunostaining for TIMP-4 was observed throughout the neointima, media, and adventitia of injured arteries. Western blot analysis confirmed the quantitative increase in TIMP-4 protein at 7 and 14 days. In situ hybridization detected increased expression of TIMP-4 as early as 24 hours after injury and a marked induction in neointimal cells 7 days after injury. We then studied the effect of TIMP-4 protein on the migration of smooth muscle cells through a matrix-coated membrane in vitro and demonstrated a 53% reduction in invasion of rat vascular smooth muscle cells. These data and the temporal relationship between the upregulation of TIMP-4, its accumulation, and the onset of collagen deposition suggest an important role for TIMP-4 in the proteolytic balance of the vasculature controlling both smooth muscle migration and collagen accumulation in the injured arterial wall.