Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells

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 α1(I), transforming growth factor β-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.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.Hepatic stellate cells (HSC) are responsible for the storage of retinoid and the control of sinusoidal blood flow in normal liver. In liver injury, HSC number is markedly increased and transformed into myofibroblast-like cells, termed activated HSC. Activated HSC produce extracellular matrix components, matrix metalloproteinases and their inhibitors [1-3]. All of them decreasing during the resolution of the fibrotic tissue.Endothelin (ET)-1, a 21 amino acid peptide, plays multifunctional roles in a variety of tissues and cells [4,5]. In the liver, ET-1 induces vascular constriction and stimulates glycogenolysis and the synthesis of lipid mediators [6,7]. ET-1 is secreted by sinusoidal endothelial cells and by activated HSC [8], and activated HSC that express high numbers of ET receptors [1] respond to ET-1 with spreading and expression of α-smooth muscle act