title: Plasmin induces intercellular adhesion molecule 1 expression in human endothelial cells via nuclear factor-κB/mitogen-activated protein kinases-dependent pathways.
abstract: 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)-κB signaling, and phosphorylation of MAP kinases p38 and ERK1/2. Further, plasmin stimulates the NF-κB/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-κB signaling as revealed by immunofluorescence staining for phosphorylated IκBα. In addition, plasma of patients with advanced atherosclerosis exhibited enhanced plasmin activity and up-regulated levels of plasmin-α2-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.
authors.affiliation: State Key Laboratory of Medical Genomics and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
authors.forename: Jiazeng
authors.initials: J
authors.lastname: Ding
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Xu
authors.forename: Wendong
authors.initials: W
authors.lastname: Chen
authors.forename: Dingliang
authors.initials: D
authors.lastname: Zhu
authors.forename: Pingjin
authors.initials: P
authors.lastname: Gao
mesh_terms: D017306:Annexin A2 / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D005263:Femoral Artery / Q000473:pathology; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000473:pathology; D015398:Signal Transduction
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases; D005341:Fibrinolysin