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.


OBJECTIVE
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.
Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.
Dong Chan
DC
Kim
Dae Won
DW
Jun
Young Il
YI
Kwon
Kang Nyeong
KN
Lee
Hang Lak
HL
Lee
Oh Young
OY
Lee
Byung Chul
BC
Yoon
Ho Soon
HS
Choi
Eun Kyung
EK
Kim
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007650:Ketanserin / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016713:Ritanserin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology; D013853:Thioacetamide; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044402:Receptor, Serotonin, 5-HT2A; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D058830:Serotonin 5-HT2 Receptor Antagonists; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D013386:Succinates; D016212:Transforming Growth Factor beta; D013853:Thioacetamide; D016713:Ritanserin; C064294:sarpogrelate; D007650:Ketanserin