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Medientyp:
E-Artikel
Titel:
Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells
Beteiligte:
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.
Erschienen:
Proceedings of the National Academy of Sciences, 2006
Erschienen in:
Proceedings of the National Academy of Sciences, 103 (2006) 16, Seite 6326-6331
Sprache:
Englisch
DOI:
10.1073/pnas.0601223103
ISSN:
1091-6490;
0027-8424
Entstehung:
Anmerkungen:
Beschreibung:
Cysteinyl leukotrienes (cysLT), i.e., LTC 4 , LTD 4 , and LTE 4 , are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT 1 -R/cysLT 2 -R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT 2 -Rs, their role in vascular biology remains to be fully understood. To delineate cysLT 2 -R actions, we stimulated human umbilical vein EC with LTD 4 and determined early induced genes. We also compared LTD 4 effects with those induced by thrombin that binds to protease-activated receptor (PAR)-1. Stringent filters yielded 37 cysLT 2 -R- and 34 PAR-1-up-regulated genes (>2.5-fold stimulation). Most LTD 4 -regulated genes were also induced by thrombin. Moreover, LTD 4 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 ≈60 min, were unaffected by a cysLT 1 -R antagonist, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD 4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus; LTD 4 up-regulated IL-8 formation and secretion; and LTD 4 raised TF protein and TF-dependent EC procoagulant activity. These data show that cysLT 2 -R activation results in a proinflammatory EC phenotype. Because LTD 4 and thrombin are likely to be formed concomitantly in vivo , cysLT 2 -R and PAR-1 may cooperate to augment vascular injury.