Plasmin induces intercellular adhesion molecule 1 expression in human endothelial cells via nuclear factor-κB/mitogen-activated protein kinases-dependent pathways
Plasmin induces intercellular adhesion molecule 1 expression in human endothelial cells via nuclear factor-κB/mitogen-activated protein kinases-dependent pathways
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DOI：
10.1177/1535370212473700
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发表时间：
2013-02-01
影响因子：
3.2
通讯作者：
Gao, Pingjin
中科院分区：
文献类型：
--
作者：
Li, Qun;Syrovets, Tatiana;Gao, Pingjin
促炎刺激物激活内皮细胞（EC）触发细胞表面上细胞粘附分子（包括细胞间粘附分子1（ICAM-1））的表达。这些分子介导炎性细胞的跨内皮迁移，这是动脉粥样硬化形成的早期关键步骤。我们以前已经证明，纤溶酶激活人类炎症细胞通过膜联蛋白A2异四聚体（A2 t）。在这里，我们表明，人脐静脉内皮细胞（HUVECs）和人微血管内皮细胞表达大量的A2 t，如蛋白质印迹，荧光显微镜和流式细胞术所示。纤溶酶激活HUVEC导致受体复合物的膜联蛋白A2亚基裂解，随后Akt/核因子（NF）-κ B信号转导激活，MAP激酶p38和ERK 1/2磷酸化。此外，纤溶酶刺激HUVEC的ICAM-1的NF-κ B/p38依赖性表达。当膜联蛋白A2被小干扰RNA下调时，纤溶酶诱导的细胞活化被取消。在体内，我们显示了内皮细胞标记物CD 31与人股动脉粥样硬化斑块中的纤溶酶受体A2 t和ICAM-1的共定位，其也表现出激活的NF-κ B信号传导，如磷酸化I κ B α的免疫荧光染色所示。此外，晚期动脉粥样硬化患者的血浆表现出增强的纤溶酶活性和上调的纤溶酶-α 2-抗纤溶酶水平。这些数据指出了纤溶酶在EC生物学中以前未被认识到的功能作用，这可能与动脉粥样硬化的发展特别相关。
Activation of endothelial cells (ECs) by proinflammatory stimuli triggers expression of cellular adhesion molecules including intercellular adhesion molecule 1 (ICAM-1) on the cell surface. Such molecules mediate the transendothelial migration of inflammatory cells, which is an early key step of atherogenesis. We have previously demonstrated that plasmin activates human inflammatory cells via the annexin A2 heterotetramer (A2t). Here we show that human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells express high amounts of A2t, as shown by Western blotting, fluorescence microscopy and flow cytometry. Activation of HUVEC by plasmin led to cleavage of the annexin A2 subunit of the receptor complex, followed by the activation of Akt/nuclear factor (NF)-kappa B signaling, and phosphorylation of MAP kinases p38 and ERK1/2. Further, plasmin stimulates the NF-kappa B/p38-dependent expression of ICAM-1 by HUVEC. The plasmin-induced activation of cells was abolished when annexin A2 was down-regulated by small-interfering RNA. In vivo, we show co-localization of the ECs marker CD31 with the plasmin receptor A2t and ICAM-1 in human atherosclerotic plaques of human femoral arteries, which also exhibit activated NF-kappa B signaling as revealed by immunofluorescence staining for phosphorylated I kappa B alpha. In addition, plasma of patients with advanced atherosclerosis exhibited enhanced plasmin activity and up-regulated levels of plasmin-alpha 2-antiplasmin. These data point to a previously unrecognized functional role of plasmin in EC biology, which could be of particular relevance in the development of atherosclerosis.