Pathogenic Aβ induces the expression and activation of matrix metalloproteinase-2 in human cerebrovascular smooth muscle cells
Pathogenic Aβ induces the expression and activation of matrix metalloproteinase-2 in human cerebrovascular smooth muscle cells
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DOI：
10.1046/j.1471-4159.2003.01745.x
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发表时间：
2003-06-01
影响因子：
4.7
通讯作者：
Van Nostrand, WE
中科院分区：
文献类型：
--
作者：
Jung, SS;Zhang, WB;Van Nostrand, WE
脑淀粉样血管病（CAA）是阿尔茨海默病及相关疾病的主要病理特征。与CAA密切相关的人脑血管平滑肌（HCSM）细胞已被用作体外模型系统来研究与淀粉样β蛋白（Abeta）的病理相互作用。以前，我们已经表明，致病形式的Abeta诱导HCSM细胞中的几种病理反应，包括在细胞表面的原纤维组装，在Abeta前体的水平增加，和凋亡性细胞死亡。在这里，我们表明，致病性Abeta刺激基质金属蛋白酶-2（MMP-2）的表达和激活。此外，我们证明，MMP-2激活的增加主要是由膜型-1（MT 1）-MMP表达（主要MMP-2激活剂）的增加引起的。最后，用MMP-2抑制剂处理导致在致病性Abeta存在下HCSM细胞活力增加。我们的研究结果表明，MMP-2的表达和激活的增加可能有助于HCSM细胞死亡的致病性Abeta。此外，这些活动也可能导致CAA中血管壁完整性的丧失，从而导致出血性卒中。因此，进一步了解MMPs在HCSM细胞变性中的作用可能有助于设计治疗策略来治疗AD和相关疾病中发现的CAA。
Cerebral amyloid angiopathy (CAA) is a major pathological feature of Alzheimer's disease and related disorders. Human cerebrovascular smooth muscle (HCSM) cells, which are intimately associated with CAA, have been used as an in vitro model system to investigate pathologic interactions with amyloid beta protein (Abeta). Previously we have shown that pathogenic forms of Abeta induce several pathologic responses in HCSM cells including fibril assembly at the cell surface, increase in the levels of Abeta precursor, and apoptotic cell death. Here we show that pathogenic Abeta stimulates the expression and activation of matrix metalloproteinase-2 (MMP-2). Furthermore, we demonstrate that the increase in MMP-2 activation is largely caused by increased expression of membrane type-1 (MT1)-MMP expression, the primary MMP-2 activator. Finally, treatment with MMP-2 inhibitors resulted in increased HCSM cell viability in the presence of pathogenic Abeta. Our findings suggest that increased expression and activation of MMP-2 may contribute to HCSM cell death in response to pathogenic Abeta. In addition, these activities may also contribute to loss of vessel wall integrity in CAA resulting in hemorrhagic stroke. Therefore, further understanding into the role of MMPs in HCSM cell degeneration may facilitate designing therapeutic strategies to treat CAA found in AD and related disorders.