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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:
National Academy of Sciences, 2006
Erschienen in:
Proceedings of the National Academy of Sciences of the United States of America, 103 (2006) 16, Seite 6326-6331
Sprache:
Englisch
ISSN:
0027-8424
Entstehung:
Anmerkungen:
Beschreibung:
<p>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 ≈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.</p>