Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors
| Autor: | C Serradeil-Le Gal, V Iourgenko, Ariane Mallat, D A Brenner, Philippe Mavier, Laura Fouassier, Danielle Raufaste, Sophie Lotersztajn, Daniel Dhumeaux, Anne-Marie Preaux, C Bradham, Cyrille Gallois, Jacques Maclouf |
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| Rok vydání: | 1996 |
| Předmět: |
medicine.medical_specialty
Ibuprofen Viper Venoms Biology Adenylyl cyclase chemistry.chemical_compound Genes jun Internal medicine Adipocytes Cyclic AMP medicine Humans Cyclic adenosine monophosphate RNA Messenger Receptor Cells Cultured Binding Sites Forskolin Endothelin-1 Receptors Endothelin Colforsin General Medicine Epoprostenol Receptor Endothelin B Endothelin 1 Up-Regulation Cell biology Endocrinology Liver chemistry Prostaglandins cardiovascular system Hepatic stellate cell cAMP-dependent pathway Endothelin receptor Protein Kinases Cell Division Adenylyl Cyclases Research Article |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci119103 |
| Popis: | During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype, proliferate, and synthetize fibrosis components. We have shown that endothelin-1 (ET-1) inhibits the proliferation of activated human HSC via endothelin B (ETB) receptors. We now investigate the transduction pathway involved in the growth inhibitory effect of ET-1 in activated HSC. Endothelin-1 and the ETB receptor agonist, sarafotoxin-S6C, increased synthesis of PGI2 and PGE2, leading to elevation of cAMP. The cyclooxygenase inhibitor ibuprofen and the adenylyl cyclase inhibitor SQ22536 both blunted the growth inhibitory effect of ET-1. Analysis of early steps associated with growth inhibition indicated that: (a) similar to ET-1, forskolin decreased c-jun mRNA induction without affecting c-fos and krox 24 mRNA expression; (b) ET-1, sarafotoxin-S6C, as well as forskolin, reduced activation of both c-Jun kinase and extracellular signal-regulated kinase. Finally, forskolin, PGI2, and PGE2 raised by fivefold the number of ET binding sites after 6 h, and increased the proportion of ETB receptors from 50% in control cells to 80% in treated cells. In conclusion, ET-1 inhibits proliferation of activated HSC via ETB receptors, through a prostaglandin/cAMP pathway that leads to inhibition of both extracellular signal-regulated kinase and c-Jun kinase activities. Upregulation of ETB receptors by prostaglandin/cAMP raises the possibility of a positive feedback loop that would amplify the growth inhibitory response. These results suggest that ET-1 and agents that increase cAMP might be of interest to limit proliferation of activated HSC during chronic liver diseases. |
| Databáze: | OpenAIRE |
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