Urokinase-type plasminogen activator receptor is involved in mediating the apoptotic effect of cleaved high molecular weight kininogen in human endothelial cells
Urokinase-type plasminogen activator receptor is involved in mediating the apoptotic effect of cleaved high molecular weight kininogen in human endothelial cells
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DOI：
10.1161/01.res.0000126567.75232.46
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发表时间：
2004-05-14
影响因子：
20.1
通讯作者：
Colman, RW
中科院分区：
文献类型：
--
作者：
Cao, DJ;Guo, YL;Colman, RW
切割的高分子量激肽原（HKa）已被证明能抑制体内新生血管形成并诱导内皮细胞凋亡。我们已经表明，HKA诱导的细胞凋亡与其抗粘附作用，并调节细胞外基质（ECM）蛋白。在这项研究中，我们确定尿激酶型纤溶酶原激活剂受体（uPAR）是内皮细胞表面HKa活性的靶点。抗-uPAR抗体阻断了HKa的凋亡作用。进一步的研究表明，uPAR在内皮细胞中形成含有整合素α（v）β（3）或α（5）β（1）、小窝蛋白和Src激酶Yes的信号复合物。HKa以抑制其凋亡作用的方式物理破坏该复合物的形成。对于第一次，我们的研究结果提供了一个机械的解释，以前的观察，HKa选择性诱导细胞凋亡的玻连蛋白上生长的内皮细胞，但不是细胞生长的纤连蛋白。这些数据也解决了有争议的作用，uPAR介导的凋亡和抗粘附活性的HKA。
Cleaved high molecular weight kininogen (HKa) has been shown to inhibit in vivo neovascularization and induce apoptosis of endothelial cells. We have shown that HKa-induced apoptosis correlated with its antiadhesive effect and was regulated by extracellular matrix (ECM) proteins. In this study, we identified the urokinase-type plasminogen activator receptor ( uPAR) as a target of HKa activity at the endothelial cell surface. Anti-uPAR antibodies blocked the apoptotic effect of HKa. Further studies revealed that uPAR formed a signaling complex containing integrin alpha(v)beta(3) or alpha(5)beta(1), caveolin, and Src kinase Yes in endothelial cells. HKa physically disrupted the formation of this complex in a manner that paralleled its apoptotic effect. For the first time, our results provide a mechanistic explanation for the previous observation that HKa selectively induces apoptosis of endothelial cells grown on vitronectin, but not cells grown on fibronectin. These data also resolve the controversial role of uPAR in mediating the apoptotic and antiadhesive activities of HKa.