Antifibrotic effects of ambrisentan,an endothelin-A receptor antagonist,in a non-alcoholic steatohepatitis mouse model |
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Authors: | Toshiaki Okamoto Masahiko Koda Kennichi Miyoshi Takumi Onoyama Manabu Kishina Tomomitsu Matono Takaaki Sugihara Keiko Hosho Junichi Okano Hajime Isomoto Yoshikazu Murawaki |
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Institution: | Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, JapanMasahiko Koda, Second Department of Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan |
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Abstract: | AIM: To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model.
METHODS: Fatty liver shionogi (FLS) FLS-ob/ob mice (male, 12 wk old) received ambrisentan (2.5 mg/kg orally per day; n = 8) or water as a control (n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver.
RESULTS: In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group (18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group (0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related mRNA expression in the liver were not significantly different between the groups.
CONCLUSION: Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis. |
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Keywords: | Endothelin Ambrisentan Steatohepatitis Hepatic stellate cell Hepatic fibrosis Oxidative stress Hepatic hydroxyproline |
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