Activated protein C decreases tumor necrosis factor related apoptosis-inducing ligand by an EPCR- independent mechanism involving Egr-1/Erk-1/2 activation

Background- APC is an antithrombotic and antiinflammatory serine protease that plays an important role in vascular function. We report that APC can suppress the proapoptotic mediator TRAIL in human umbilical vein endothelial cells, and we have investigated the signaling mechanism. APC inhibited endo...

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Published in:	Arteriosclerosis, thrombosis, and vascular biology Vol. 27; no. 12; p. 2634
Main Authors:	O'Brien, Lee A, Richardson, Mark A, Mehrbod, Sean F, Berg, David T, Gerlitz, Bruce, Gupta, Akanksha, Grinnell, Brian W
Format:	Journal Article
Language:	English
Published:	United States 01.12.2007
Subjects:	Antigens, CD - genetics Antigens, CD - metabolism Cells, Cultured Cytoprotection Early Growth Response Protein 1 - metabolism Endothelial Cells - enzymology Endothelial Cells - metabolism Endothelial Protein C Receptor Enzyme Activation Humans Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Phosphorylation Phosphotransferases (Alcohol Group Acceptor) - genetics Phosphotransferases (Alcohol Group Acceptor) - metabolism Protein C - metabolism Receptor, PAR-1 - metabolism Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Receptors, Lysosphingolipid - metabolism RNA Interference RNA, Messenger - metabolism RNA, Small Interfering - metabolism Signal Transduction Time Factors TNF-Related Apoptosis-Inducing Ligand - genetics TNF-Related Apoptosis-Inducing Ligand - metabolism Transcription, Genetic Tumor Necrosis Factor-alpha - metabolism
ISSN:	1524-4636, 1524-4636
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Summary:	Background- APC is an antithrombotic and antiinflammatory serine protease that plays an important role in vascular function. We report that APC can suppress the proapoptotic mediator TRAIL in human umbilical vein endothelial cells, and we have investigated the signaling mechanism. APC inhibited endothelial TRAIL expression and secretion and its induction by cell activation. To explore the mechanism, we examined factors associated with TRAIL regulation and demonstrated that APC increased the level of EGR-1, a transcriptional factor known to suppress the TRAIL promoter. APC also induced a significant increase in phosphorylation of ERK-1/2, required to activate EGR-1 expression. Activation of ERK-1/2 was dependent on the protease activated receptor-1 (PAR-1), but independent of the endothelial protein C receptor (EPCR). Using siRNA, we found that the effect of APC on the EGR-1/ERK signaling required for TRAIL inhibition was dependent on the S1P1 receptor and S1P1 kinase. Our data suggest that APC may provide cytoprotective activity by activating the ERK pathway, which upregulates EGR-1 thereby suppressing the expression of TRAIL. Moreover, we provide evidence that APC can induce a cell signaling response through a PAR-1/S1P1-dependent but EPCR-independent mechanism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1524-4636 1524-4636
DOI:	10.1161/ATVBAHA.107.153734