Amyloid β-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells
Amyloid β-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells
复制标题
DOI：
10.1074/jbc.m301398200
复制
发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Van Nostrand, WE
中科院分区：
文献类型：
--
作者：
Davis, J;Wagner, MR;Van Nostrand, WE
纤维状淀粉样β蛋白（Abeta）在脑血管中的积累，一种称为脑淀粉样血管病（CAA）的病症，是阿尔茨海默病和某些相关疾病的关键病理特征，并且与体内和体外脑血管细胞死亡密切相关。此外，严重的CAA导致血管壁完整性的丧失和脑出血。虽然CAA后一种病理结果的基础仍未解决，但可能涉及局部蛋白水解机制的改变。在这里，我们表明，致病形式的Abeta刺激表达纤溶酶原激活剂活性在培养的人脑血管平滑肌（HCSM）细胞，CAA的体外模型。核糖核酸酶保护试验和纤溶酶原酶谱表明，尿激酶型纤溶酶原激活剂（uPA）是负责这一活动。HCSM细胞表面上的uPA有优先积累，这是通过伴随的uPA受体表达的增加来介导的。在存在纤溶酶原的情况下，存在添加到HCSM细胞中的Abeta的稳健降解，导致细胞活力的恢复。这表明uPA的表达增加最初可能作为一种保护机制，导致致病刺激物Abeta的局部降解和清除。另一方面，uPA的慢性表达和纤溶酶原激活导致HCSM细胞附着的严重丧失。这表明，在脑血管壁中的体内类似的延长效应可能导致CAA中的完整性丧失和脑出血。
The accumulation of fibrillar amyloid-beta protein (Abeta) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), is a key pathological feature of Alzheimer's disease and certain related disorders and is intimately associated with cerebrovascular cell death both in vivo and in vitro. Moreover, severe CAA leads to loss of vessel wall integrity and cerebral hemorrhage. Although the basis for these latter pathological consequences in CAA remains unresolved alterations in local proteolytic mechanisms may be involved. Here we show that pathogenic forms of Abeta stimulate the expression of plasminogen activator activity in cultured human cerebrovascular smooth muscle (HCSM) cells, an in vitro model of CAA. RNase protection assays and plasminogen zymography showed that urokinase-type plasminogen activator (uPA) was responsible for this activity. There was preferential accumulation of uPA on the HCSM cell surface that was mediated through a concomitant increase in expression of the uPA receptor. In the presence of plasminogen there was robust degradation of Abeta that was added to the HCSM cells resulting in restoration of cell viability. This suggests that increased expression of uPA may initially serve as a protective mechanism leading to localized degradation and clearance of the pathogenic stimulus Abeta. On the other hand, chronic expression of uPA and plasminogen activation led to a profound loss of HCSM cell attachment. This suggests that a similar prolonged effect in vivo in the cerebral vessel wall may contribute to loss of integrity and cerebral hemorrhage in CAA.