Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells.
Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells.
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DOI：
10.1186/1476-5926-5-5
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发表时间：
2006-10-24
期刊：
影响因子：
--
通讯作者：
Murawaki Y
中科院分区：
文献类型：
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作者：
Koda M;Bauer M;Krebs A;Hahn EG;Schuppan D;Murawaki Y
在肝损伤中，肝星状细胞（HSC）池增加并产生细胞外基质蛋白，在纤维化消退期间减少。内皮素-1（ET-1）在肝纤维化中的促纤维化作用仍有争议。因此，我们研究了ET-1对HSC增殖、凋亡和促纤维化基因表达的影响。第1代HSC主要表达内皮素A受体（ETAR）mRNA，第4代HSC主要表达内皮素B受体（ETBR）mRNA。ET-1对第1代HSC的DNA合成无影响，但对第4代HSC的DNA合成有50%以上的抑制作用。ETBR特异性拮抗剂BQ 788可阻断内皮素-1对细胞增殖的抑制作用，表明ETBR在细胞生长抑制中具有重要作用。ET-1对血清剥夺或Fas配体诱导的第1代或第4代HSC凋亡无明显抑制作用。ET-1可浓度依赖性地增加第1代HSC中前胶原α1（I）、转化生长因子β 1和基质金属蛋白酶（MMP）2的mRNA转录，但对第4代HSC无明显影响。前纤维化基因表达被ETAR拮抗剂BQ 123废除。BQ 123和BQ 788均能抑制ET-1引起的MMP-2表达的增加。我们发现ET-1刺激第1代HSC的纤维化基因表达，并抑制第4代HSC的HSC增殖。这些数据表明ET-1对HSC的促纤维化和抗纤维化作用参与了肝纤维化的过程。
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. 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.