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

J Clin Invest. 1996 Dec 15;98(12):2771-8. doi: 10.1172/JCI119103.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Adipocytes / metabolism*
  • Binding Sites
  • Cell Division / drug effects*
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP / pharmacology*
  • Endothelin-1 / pharmacology*
  • Epoprostenol / analogs & derivatives
  • Epoprostenol / metabolism
  • Epoprostenol / pharmacology
  • Genes, jun / genetics
  • Humans
  • Ibuprofen / pharmacology
  • Liver / metabolism
  • Prostaglandins / metabolism
  • Protein Kinases / metabolism
  • RNA, Messenger / metabolism
  • Receptor, Endothelin B
  • Receptors, Endothelin / metabolism
  • Up-Regulation / physiology
  • Viper Venoms / pharmacology


  • Endothelin-1
  • Prostaglandins
  • RNA, Messenger
  • Receptor, Endothelin B
  • Receptors, Endothelin
  • Viper Venoms
  • sarafotoxins s6
  • Colforsin
  • carboprostacyclin
  • Epoprostenol
  • Cyclic AMP
  • Protein Kinases
  • Adenylyl Cyclases
  • Ibuprofen