title: Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells.
abstract: BACKGROUND
  In liver injury, the pool of hepatic stellate cell (HSC) increases and produces extracellular matrix proteins, decreasing during the resolution of fibrosis. The profibrogenic role of endothelin-1 (ET-1) in liver fibrosis remains disputed. We therefore studied the effect of ET-1 on proliferation, apoptosis and profibrogenic gene expression of HSCs.
  
  
  RESULTS
  First passage HSC predominantly expressed endothelin A receptor (ETAR) mRNA and 4th passage HSC predominantly expressed the endothelin B receptor (ETBR) mRNA. ET-1 had no effect on DNA synthesis in 1st passage HSC, but reduced DNA synthesis in 4th passage HSC by more than 50%. Inhibition of proliferation by endothelin-1 was abrogated by ETBR specific antagonist BQ788, indicating a prominent role of ETBR in growth inhibition. ET-1 did not prevent apoptosis induced by serum deprivation or Fas ligand in 1st or 4th passage HSC. However, ET-1 increased procollagen alpha1(I), transforming growth factor beta-1 and matrix metalloproteinase (MMP)-2 mRNA transcripts in a concentration-dependent manner in 1st, but not in 4th passage HSC. Profibrogenic gene expression was abrogated by ETAR antagonist BQ123. Both BQ123 and BQ788 attenuated the increase of MMP-2 expression by ET-1.
  
  
  CONCLUSIONS
  We show that ET-1 stimulates fibrogenic gene expression for 1st passage HSC and it inhibits HSC proliferation for 4th passage HSC. These data indicate the profibrogenic and antifibrogenic action of ET-1 for HSC are involved in the process of liver fibrosis.
authors.affiliation: First Department of Medicine, University of Erlangen-Nuernberg, Erlangen, Germany. masakoda@grape.med.tottori-u.ac.jp
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Anja
authors.initials: A
authors.lastname: Krebs
authors.forename: Eckhart G
authors.initials: EG
authors.lastname: Hahn
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki