5-HT2A receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis

Background 5‐hydroxytryptamine (5‐HT) receptors are upregulated in activated hepatic stellate cells (HSCs), and are therefore thought to play an important role in their activation. Aim The aim of this study was to determine whether 5‐HT2A receptor antagonists affect the activation or apoptosis of HS...

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Published in:Liver international 2013-04, Vol.33 (4), p.535-543
Main Authors: Kim, Dong Chan, Jun, Dae Won, Kwon, Young Il, Lee, Kang Nyeong, Lee, Hang Lak, Lee, Oh Young, Yoon, Byung Chul, Choi, Ho Soon, Kim, Eun Kyung
Format: Article
Language:English
Subjects:
5-HT
5-HT2A receptor
Actins - metabolism
Animals
Apoptosis - drug effects
Cell Line
Cell Survival - drug effects
Collagen Type I - metabolism
Dose-Response Relationship, Drug
fibrosis
hepatic stellate cell
Hepatic Stellate Cells - drug effects
Hepatic Stellate Cells - metabolism
Hepatic Stellate Cells - pathology
Humans
Ketanserin - pharmacology
Liver Cirrhosis, Experimental - chemically induced
Liver Cirrhosis, Experimental - drug therapy
Liver Cirrhosis, Experimental - metabolism
Liver Cirrhosis, Experimental - pathology
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species - metabolism
Receptor, Serotonin, 5-HT2A - drug effects
Receptor, Serotonin, 5-HT2A - genetics
Receptor, Serotonin, 5-HT2A - metabolism
Ritanserin - pharmacology
RNA, Messenger - metabolism
sarpogrelate
Serotonin 5-HT2 Receptor Antagonists - pharmacology
Smad2 Protein - metabolism
Smad3 Protein - metabolism
Succinates - pharmacology
Thioacetamide
Time Factors
Transforming Growth Factor beta - metabolism
Wound Healing - drug effects
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Summary:Background 5‐hydroxytryptamine (5‐HT) receptors are upregulated in activated hepatic stellate cells (HSCs), and are therefore thought to play an important role in their activation. Aim The aim of this study was to determine whether 5‐HT2A receptor antagonists affect the activation or apoptosis of HSCs in vitro and/or in vivo. Methods For the in vitro experiments, the viability, apoptosis and wound healing ability of LX‐2 cells were examined after treatment with various 5‐HT2A receptor antagonists. Levels of HSC activation markers (procollagen type I, α‐SMA, TGF‐β and Smad 2/3) were measured. For in vivo experiments, rats were divided into three groups: (i) a control group, (ii) a disease group, in which cirrhosis was induced by thioacetamide (iii) a treatment group, in which cirrhosis was induced and a 5‐HT2A receptor antagonist (sarpogrelate, 30 mg/kg) was administered. Results 5‐HT2A, but not 5‐HT2B receptor mRNA increased with time upon HSC activation. 5‐HT2A receptor antagonists (ketanserin and sarpogrelate) inhibited viability and wound healing in LX‐2 cells and induced apoptosis. Expression of α‐SMA and procollagen type I was also inhibited. In the in vivo study, lobular inflammation was reduced in the sarpogrelate‐treated group, but there was only slight and statistically insignificant attenuation of periportal fibrosis. Expression of α‐SMA, TGF‐β and Smad 2/3 was also reduced in the treatment group. Conclusions 5‐HT2A receptor antagonists can reduce inflammation and the activation of HSCs in this cirrhotic model.
ISSN:1478-3223
1478-3231
DOI:10.1111/liv.12110