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Related Collections Signal Transduction Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2002, Vol. 99, No. 1, pp. 199-206 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/NFAT Valery N. Bochkov, Diana Mechtcheriakova, Marcus Lucerna, Joakim Huber, Roland Malli, Wolfgang F. Graier, Erhard Hofer, Bernd R. Binder, and Norbert Leitinger From the Department of Vascular Biology and Thrombosis Research, University of Vienna, Austria, and Department of Medical Biochemistry and Medical Molecular Biology, University of Graz, Austria. Activation of endothelial cells by lipid oxidation products is a key event in the initiation and progression of the atherosclerotic lesion. Minimally modified low-density lipoprotein (MM-LDL) induces the expression of certain inflammatory molecules such as tissue factor (TF) in endothelial cells. This study examined intracellular signaling pathways leading to TF up-regulation by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a biologically active component of MM-LDL. OxPAPC induced TF activity and protein expression in human umbilical vein endothelial cells (HUVECs). However, OxPAPC neither induced phosphorylation or degradation of IB nor DNA binding of nuclear factor-B (NF-B). Furthermore, OxPAPC-induced TF expression was not inhibited by overexpression of IB. These results strongly indicate that OxPAPC-induced TF expression is independent of the classical NF-B pathway. However, OxPAPC stimulated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and expression of early growth response factor 1 (EGR-1). Inhibitors of mitogen-activated kinase/ERK (MEK) or protein kinase C (PKC) blocked elevation of both EGR-1 and TF. Furthermore, overexpression of NAB2, a corepressor of EGR-1, inhibited effects of OxPAPC. In addition, OxPAPC induced rapid and reversible elevation of free cytosolic Ca++ levels and nuclear factor of activated T cells (NFAT)/DNA binding. Induction of TF expression by OxPAPC was partially inhibited by cyclosporin A, known to block calcineurin, a Ca++-dependent phosphatase upstream of NFAT. Treatment of OxPAPC with phospholipase A2 destroyed its biologic activity and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine was identified as one biologically active component of OxPAPC that induces TF expression. Together, the results demonstrate that OxPAPC induces TF expression in HUVECs through activation of PKC/ERK/EGR-1 and Ca++/calcineurin/NFAT pathways rather than by NF-B-mediated transcription. Thus, oxidized phospholipids may contribute to inflammation by activating pathways alternative to the classical NF-B pathway. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: O. V. Oskolkova, T. Afonyushkin, A. Leitner, E. von Schlieffen, P. S. Gargalovic, A. J. Lusis, B. R. Binder, and V. N. Bochkov ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response Blood, July 15, 2008; 112(2): 330 - 339. [Abstract] [Full Text] [PDF] M. Waldeck-Weiermair, C. Zoratti, K. Osibow, N. Balenga, E. Goessnitzer, M. Waldhoer, R. Malli, and W. F. Graier Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression J. Cell Sci., May 15, 2008; 121(10): 1704 - 1717. 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