In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 16 ( 2006-04-18), p. 6326-6331
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0601223103
Sprache:
Englisch
Verlag:
Proceedings of the National Academy of Sciences
Publikationsdatum:
2006
ZDB Id:
209104-5
ZDB Id:
1461794-8
SSG:
11
SSG:
12
