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 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.
Uzonyi
Barbara
B
Institute for Vascular Medicine aud Institute for Medical Statistics, Computer Sciences, and Documentation, Friedrich-Schiller University, Bachstrasse 18, 07743 Jena, Germany.
Lötzer
Katharina
K
Jahn
Steffen
S
Kramer
Cornelia
C
Hildner
Markus
M
Bretschneider
Ellen
E
Radke
Dörte
D
Beer
Michael
M
Vollandt
Rüdiger
R
Evans
Jilly F
JF
Funk
Colin D
CD
Habenicht
Andreas J R
AJ
D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000819:agonists / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000819:agonists / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear; D018077:Receptors, Leukotriene / Q000819:agonists / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology
D008565:Membrane Proteins; D044463:Receptor, PAR-1; D018160:Receptors, Cytoplasmic and Nuclear; D018077:Receptors, Leukotriene; D017997:Leukotriene C4; C412375:cysteinyl leukotriene receptor 2; D013917:Thrombin