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5-HT2Areceptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis
- Source :
- Liver International. 33:535-543
- Publication Year :
- 2013
- Publisher :
- Wiley, 2013.
-
Abstract
- 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, a-SMA, TGF-b 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 a-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 a-SMA, TGF-b 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. The total amount of 5-hydroxytryptamine (5-HT, also known as serotonin) in the human body is around 10 mg, with approximately 95% of this in the gastrointestinal tract and the remaining 5% in the brain (1). It is secreted by enterochromaffin cells into the blood, where it is actively taken up by platelets (2). It is involved in a variety of functions such as regulation of emotion, appetite, sleep, gastrointestinal motility, secretion, vascular contraction, relaxation and platelet aggregation (3, 4). 5-HT has an important role in proliferation of hepatocytes as reported in recent studies. 5-HT secreted from platelets was found to play an important role in the regeneration of hepatocytes (5, 6). Recently, Nagao et al. demonstrated an involvement of 5-HT in the thrombocytotic effect in splenectomy-induced liver regeneration, and in the amelioration of fibrosis in rat liver with secondary biliary cirrhosis (6). Tian et al. showed that 5-HT could prevent small-for-size liver graft failure in mice by enhancing hepatocyte regeneration via the IL-6 pathway (7). These studies are consistent with previous work demonstrating that platelets promote liver regeneration (5). These evidences indicate that 5-HT has protective role against hepatic ischaemic and reperfusion injury. Until now most studies have focused on the promotion of hepatic regeneration by 5-HT via preservation of the hepatic microcirculation and IL-6 pathway, but 5-HT has other effects on the liver. For example, the increased levels of reactive oxygen species produced by 5-HT degradation aggravate steatohepatitis (8), and expression of 5-HT receptors is upregulated in activated HSCs (9). This interesting pleiotropic influence of 5-HT on the liver suggested that comprehensive investigation of its cell type specific expression patterns and its roles in various liver conditions would be valuable, along with studies involving selective blockade. There are as yet no published data on the effects of selective 5-HT blockers on in vitro or in vivo hepatic stellate cell (HSC) activation. Renal mesangial cells, which have similar properties to HSCs, produce increased levels of TGF-b and connective tissue growth factor in response to activation of 5-HT2A receptors (10–12). 5-HT2 receptors are also
- Subjects :
- medicine.medical_specialty
Time Factors
Cirrhosis
Cell Survival
medicine.drug_class
Apoptosis
Sarpogrelate
Smad2 Protein
Thioacetamide
Biology
Liver Cirrhosis, Experimental
Collagen Type I
Cell Line
Rats, Sprague-Dawley
chemistry.chemical_compound
Transforming Growth Factor beta
Internal medicine
Hepatic Stellate Cells
medicine
Animals
Humans
Receptor, Serotonin, 5-HT2A
RNA, Messenger
Smad3 Protein
Receptor
Wound Healing
Dose-Response Relationship, Drug
Hepatology
Succinates
Receptor antagonist
medicine.disease
Hepatic stellate cell activation
Actins
Liver regeneration
Rats
Endocrinology
chemistry
Ritanserin
Serotonin 5-HT2 Receptor Antagonists
Hepatic stellate cell
Ketanserin
Steatohepatitis
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 14783223
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Liver International
- Accession number :
- edsair.doi.dedup.....b2ee60b614bbefea0875cf281fe373d7