Macrophage-derived matrix metalloproteinase-2 and-9 promote the progression of cerebral aneurysms in rats
Macrophage-derived matrix metalloproteinase-2 and-9 promote the progression of cerebral aneurysms in rats
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DOI：
10.1161/01.str.0000252129.18605.c8
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发表时间：
2007-01-01
期刊：
影响因子：
8.3
通讯作者：
Hashimoto, Nobuo
中科院分区：
文献类型：
--
作者：
Aoki, Tomohiro;Kataoka, Hiroharu;Hashimoto, Nobuo
背景和目的——脑动脉瘤的发生、进展和破裂的机制尽管具有临床意义，但尚未完全了解。基质金属蛋白酶（MMP）是参与血管壁重塑的蛋白酶家族。在本研究中，我们研究了MMPs在脑动脉瘤进展中的重要性。方法-在7周大的雄性Sprague-Dawley大鼠中实验诱导脑动脉瘤。通过免疫组织化学和RT-PCR检测MMP-2和MMP-9的表达。通过原位酶谱法评估动脉瘤壁中的明胶酶活性。使用MMP-2、-9和-12的选择性抑制剂tolylsam来检测MMP-2和MMP-9的抑制效果。结果-实验诱导的大鼠脑动脉瘤的动脉壁中巨噬细胞浸润并表达MMP-2和-9。随着动脉瘤的进展，巨噬细胞浸润和MMP表达增加。大鼠脑动脉瘤动脉壁中 MMP-2 和 MMP-9 的明胶酶活性增加。此外，Tolylsam 降低了我们的大鼠模型中晚期动脉瘤的比例。结论-这些数据表明巨噬细胞衍生的 MMP-2 和 -9 可能在脑动脉瘤的进展中发挥重要作用。这项研究的结果将为脑动脉瘤的发病机制提供新的线索，并强调炎症反应导致细胞外基质变性在该疾病过程中的重要性。
Background and Purpose-Mechanisms of initiation, progression and rupture of cerebral aneurysms have not yet been fully understood despite its clinical significance. Matrix metalloproteinases (MMPs) are a family of proteinases which are involved in the remodeling of vascular walls. In the present study, we investigated the significance of MMPs in the progression of cerebral aneurysms.Methods-Cerebral aneurysms were experimentally induced in 7-week-old male Sprague-Dawley rats. MMP-2 and MMP-9 expression was examined by immunohistochemistry and RT-PCR. Gelatinase activity in aneurysmal walls was assessed by in situ zymography. A selective inhibitor for MMP-2, -9 and -12, tolylsam, was used to examine the effect of inhibition of MMP-2 and MMP-9.Results-Macrophages infiltrated in arterial walls of experimentally induced rat cerebral aneurysms and expressed MMP-2 and -9. Macrophage infiltration and MMP expression was increased with the progression of aneurysms. Gelatinase activity attributable to MMP-2 and MMP-9 increased in arterial walls of rat cerebral aneurysms. Furthermore, tolylsam reduced the ratio of advanced aneurysms in our rat model.Conclusions-These data suggest that macrophage-derived MMP-2 and -9 may play an important role in the progression of cerebral aneurysms. The findings of this study will shed a new light into the pathogenesis of cerebral aneurysms and highlight the importance of inflammatory response causing the degeneration of extracellular matrix in the process of this disease.