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内皮素-1可增强肝星状细胞中促纤维化基因的表达，但不促进其DNA合成或凋亡。

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

作者信息

Koda Masahiko, Bauer Michael, Krebs Anja, Hahn Eckhart G, Schuppan Detlef, Murawaki Yoshikazu

机构信息

First Department of Medicine, University of Erlangen-Nuernberg, Erlangen, Germany.

出版信息

Comp Hepatol. 2006 Oct 24;5:5. doi: 10.1186/1476-5926-5-5.

DOI:10.1186/1476-5926-5-5
PMID:17062135
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1635728/
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.

CONCLUSION

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.

摘要

背景

在肝损伤时，肝星状细胞（HSC）数量增多并产生细胞外基质蛋白，在纤维化消退过程中数量减少。内皮素-1（ET-1）在肝纤维化中的促纤维化作用仍存在争议。因此，我们研究了ET-1对HSC增殖、凋亡及促纤维化基因表达的影响。

结果

原代培养的HSC主要表达内皮素A受体（ETAR）mRNA，第4代培养的HSC主要表达内皮素B受体（ETBR）mRNA。ET-1对原代培养的HSC的DNA合成无影响，但使第4代培养的HSC的DNA合成减少超过50%。ETBR特异性拮抗剂BQ788可消除内皮素-1对增殖的抑制作用，表明ETBR在生长抑制中起重要作用。ET-1不能阻止血清剥夺或Fas配体诱导的原代或第4代培养的HSC凋亡。然而，ET-1在原代培养的HSC中以浓度依赖的方式增加I型前胶原α1、转化生长因子β-1和基质金属蛋白酶（MMP）-2 mRNA转录本，但在第4代培养的HSC中无此作用。ETAR拮抗剂BQ123可消除促纤维化基因表达。BQ123和BQ788均减弱了ET-1对MMP-2表达的增加作用。

结论

我们发现ET-1刺激原代培养的HSC的纤维化基因表达，并抑制第4代培养的HSC的增殖。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过程。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/316db17f27d1/1476-5926-5-5-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/98e8909a662a/1476-5926-5-5-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/86b92c8bf157/1476-5926-5-5-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/0982b8580935/1476-5926-5-5-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/28c5bd53c4f3/1476-5926-5-5-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/a10e1dc9863f/1476-5926-5-5-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/316db17f27d1/1476-5926-5-5-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/98e8909a662a/1476-5926-5-5-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/86b92c8bf157/1476-5926-5-5-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/0982b8580935/1476-5926-5-5-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/28c5bd53c4f3/1476-5926-5-5-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/a10e1dc9863f/1476-5926-5-5-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0248/1635728/316db17f27d1/1476-5926-5-5-6.jpg

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