Plasmin-induzierte Aktivierung menschlicher Endothelzellen: Signaltransduktionsmechanismen und funktionelle Bedeutung
Zusammenfassung der Projektergebnisse
Activation of endothelial cells by pro-inflammatory stimuli triggers expression of cellular adhesion molecules such as ICAM-1 on the cell surface, increased adhesion of leukocytes and their trans-endothelial migration marking the key steps in development of atherosclerosis. The serine protease plasmin is generated from its ubiquitously present zymogen during fibrinolysis but also during inflammation. The expression of fibrinolytic genes is increased in the atherosclerotic aorta and correlates with the severity of coronary lesions. We have shown that plasmin activates human inflammatory cells via the annexin A2 heterotetramer. Similar to inflammatory cells, activation of HUVEC by plasmin led to cleavage of the annexin A2 subunit of the receptor complex in lipid rafts, followed by the activation of pro-inflammatory signaling in endothelial cells. Activation of MAPK and the Akt/NF-KB signaling triggered expression of ICAM-1 on endothelial cells and release of soluble ICAM-1. Plasmin cleaves intercellular junctions and VE-cadherin in endothelial cells, inhibits the endothelial cell migration and tube formation, but has no effect on endothelial cell proliferation. DNA microarray analysis revealed plasmin-mediated induction of genes related to the eicosanoid metabolism. In vivo, in human atherosclerotic plaques of human femoral arteries, the endothelial cell marker CD31 is co-localized with the plasmin receptor annexin A2 heterotetramer and ICAM-1. Such plaques also exhibit phosphorylated IKB alpha indicating activation of the NF-KB signaling. Moreover, in advanced atherosclerosis, plasma of patients exhibited enhanced plasmin activity and up-regulated levels of plasmin-alpha2-antiplasmin complexes. These data revealed a new role of plasmin in endothelial cell biology, which could be of particular importance for the identification of new approaches for treatment of atherosclerosis.
Projektbezogene Publikationen (Auswahl)
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Plasmin triggers chemotaxis of monocyte-derived dendritic cells through an Akt2-dependent pathway and promotes a T-helper type-1 response. Arteriosclerosis, Thrombosis, and Vascular Biology,
Vol. 30. 2010, pp. 582-590.
Li X., Syrovets T., Genze F., Pitterle K., Oberhuber A., Orend K.H., Simmet T.
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Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2. Acta Pharmacol Sin, Vol. 32. 2011, Issue 11, pp. 1411–1418.
Li Q, Laumonnier Y, Syrovets T and Simmet T
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Effects of plasmin on endothelial cells. Naunyn Schmiedebergs Arch Pharmacol 2012;385:90
Maheswaran V, Schmidt Z, Koshova O, Lunov O, Syrovets T and Simmet T
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Plasmin as a proinflammatory cell activator. Journal of Leukocyte Biology, Vol. 92. 2012, no. 3, pp. 509-519.
Syrovets T, Lunov O and Simmet T
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The serine protease plasmin triggers expression of the CC-chemokine ligand 20 in dendritic cells via Akt/NF-кB-dependent pathways. Journal of Biomedicine and Biotechnology, Vol. 2012. 2012, Article ID 186710.
Li X, Syrovets T., Simmet T.
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Plasmin induces intercellular adhesion molecule 1 expression in human endothelial cells via nuclear factor-кB/mitogenactivated protein kinases-dependent pathways. Experimental Biology and Medicine, Vol. 238. 2013, no. 2, pp. 176-186.
Li Q, Syrovets T, Simmet T, Ding JZ, Xu JZ, Chen WD, Zhu DL and Gao PJ
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Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages. Acta Biochimica et Biophysica Sinica
Vol. 45. 2013, Issue 7, pp. 593-600.
Li Q., Laumonnier Y., Syrovets T., Simmet T.
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The serine protease plasmin induces expression of the CC-chemokine ligand 20 in human monocyte-derived dendritic cells. Cytokine,
Vol. 63. 2013, Issue 3, p. 281.
Li X, Syrovets T., Simmet T.
