Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

Cysteinyl leukotrienes (cysLT), i.e., LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT1-R/cysLT2-R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT2-Rs, their role in vascular biology r...

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Vydané v:	Proceedings of the National Academy of Sciences - PNAS Ročník 103; číslo 16; s. 6326
Hlavní autori:	Uzonyi, Barbara, Lötzer, Katharina, Jahn, Steffen, Kramer, Cornelia, Hildner, Markus, Bretschneider, Ellen, Radke, Dörte, Beer, Michael, Vollandt, Rüdiger, Evans, Jilly F, Funk, Colin D, Habenicht, Andreas J R
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 18.04.2006
Predmet:	Blood Coagulation - drug effects Blood Coagulation - physiology Cells, Cultured Endothelial Cells - drug effects Endothelial Cells - metabolism Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Gene Expression Regulation Humans Leukotriene C4 - metabolism Leukotriene C4 - pharmacology Membrane Proteins - agonists Membrane Proteins - physiology Receptor, PAR-1 - agonists Receptor, PAR-1 - physiology Receptors, Cytoplasmic and Nuclear Receptors, Leukotriene - agonists Receptors, Leukotriene - physiology Thrombin - metabolism Thrombin - pharmacology Transcription, Genetic - drug effects Umbilical Veins - cytology
ISSN:	0027-8424
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Shrnutí:	Cysteinyl leukotrienes (cysLT), i.e., LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT1-R/cysLT2-R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT2-Rs, their role in vascular biology remains to be fully understood. To delineate cysLT2-R actions, we stimulated human umbilical vein EC with LTD4 and determined early induced genes. We also compared LTD4 effects with those induced by thrombin that binds to protease-activated receptor (PAR)-1. Stringent filters yielded 37 cysLT2-R- and 34 PAR-1-up-regulated genes (>2.5-fold stimulation). Most LTD4-regulated genes were also induced by thrombin. Moreover, LTD4 plus thrombin augmented gene expression when compared with each agonist alone. Strongly induced genes were studied in detail: Early growth response (EGR) and nuclear receptor subfamily 4 group A transcription factors; E-selectin; CXC ligand 2; IL-8; a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1 (ADAMTS1); Down syndrome critical region gene 1 (DSCR1); tissue factor (TF); and cyclooxygenase 2. Transcripts peaked at approximately 60 min, were unaffected by a cysLT1-R antagonist, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus; LTD4 up-regulated IL-8 formation and secretion; and LTD4 raised TF protein and TF-dependent EC procoagulant activity. These data show that cysLT2-R activation results in a proinflammatory EC phenotype. Because LTD4 and thrombin are likely to be formed concomitantly in vivo, cysLT2-R and PAR-1 may cooperate to augment vascular injury.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0027-8424
DOI:	10.1073/pnas.0601223103