5‐<scp>HT</scp><sub>2A</sub> receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis

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, Min Jung

doi:10.1111/liv.12110

Cited by 40 publications

(36 citation statements)

References 32 publications

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“…Of particular relevance to portal hypertension, platelet-derived serotonin in a model of viral hepatitis results in hepatic microcirculatory dysfunction in the sinusoids leading to reduced flow [95], consistent with other studies demonstrating serotonin-mediated low sinusoidal flow reversed by serotonin receptor antagonism [96,97]. This effect may be mediated by serotonin-induced calcium influx into sinusoidal endothelial cells and myosin light chain phosphorylation causing fenestral contraction [98,99], or by serotonin-mediated HSC activation, possibly through increasing intracellular calcium [100,101].…”

Section: Plateletssupporting

confidence: 66%

Biology of portal hypertension

McConnell

Iwakiri

2017

Hepatol Int

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Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.

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Section: Plateletssupporting

confidence: 66%

Biology of portal hypertension

McConnell

Iwakiri

2017

Hepatol Int

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“…Our findings are consistent with previous studies showing that antagonists of 5HTR2A inhibit fibrosis mRNA expression in vitro in the human hepatic stellate cell line, LX2, and in vivo in rats with LF induced by thioacetamide . Also, HSC secretion of 5HT and expression of 5HTR2B contributes to activation of HSCs and enhanced LF in rats .…”

Section: Discussionsupporting

confidence: 93%

Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

Kyritsi

Chen²,

O’Brien³

et al. 2019

Hepatology

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Background and Aims Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO‐A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5‐hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile‐duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. Approach and Results While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2–/–) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO‐A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2–/–‐ mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2–/–‐ mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2–/– mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2–/– mice, respectively. 5HT levels increase in Mdr2–/– mice and in PSC human patients compared to their controls and decrease in serum of Mdr2–/– mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2–/– mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO‐A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. Conclusions Modulation of the TPH1/MAO‐A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.

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“…Recent evidence suggests that HSCs are the main source of MFs in hepatic fibrosis models, including bile duct–ligated, CCl 4 ‐treated, and thioacetamide‐treated rodents . Kim et al also showed that 5‐HT2A receptor antagonists can reduce inflammation and HSC activation in a thioacetamide‐induced liver fibrosis model. However, on the basis of 2 different models of cholestatic liver injury involving arterial liver ischemia and bile duct ligation, Beaussier et al suggested that PFs may be the predominant source of MFs in biliary fibrosis and that HSCs do not undergo MF differentiation in biliary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that 5‐HT and 5‐HT2 receptors are involved in hepatic fibrosis; for example, the 5‐HT2B receptor has been suggested to act as a marker of activated HSCs . Kim et al showed that 5‐HT has a stimulatory effect on TGF‐β1 expression in rat HSCs in the liver, and this effect can be blocked by ketanserin, a 5‐HT2A receptor antagonist. Other researchers have also reported that the 5‐HT2A receptor can promote fibrosis in some tissues by activating TGF‐β1 signaling …”

mentioning

confidence: 99%

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats

Chen

Guo

et al. 2014

Liver Transpl

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Biliary fibrosis is a major complication after donation after cardiac death (DCD) liver transplantation. In this process, the roles of serotonin [5-hydroxytryptamine (5-HT)] and the 5-HT2A receptor subtype are still unknown. In this study, we analyzed markers of portal fibroblast (PF)/myofibroblast (MF) transdifferentiation such as transforming growth factor b1 (TGF-b1), phosphorylated smad2/3, a-smooth muscle actin (a-SMA), collagen I, and collagen III in a primary culture system of PFs after the administration of 5-HT or 5-HT plus ketanserin (a selective 5-HT2A receptor antagonist). A rat DCD transplant model was established with 30 minutes of warm ischemia and 4 hours of cold ischemia during organ procurement. Recipients were intraperitoneally injected with ketanserin (1 mgÁkg 21 Áday 21 ) or normal saline. Grafts without in situ warm ischemia instead of minimal cold storage (30 minutes) served as controls. The serum biochemistry, the liver contents of 5-HT and hydroxyproline (HYP), and the expression of fibrosis-related genes (including TGF-b1, matrix metalloproteinase 2, procollagen a1, and a-SMA messenger RNA) were determined. The extent of biliary fibrosis was also assessed histopathologically. The results indicated that ketanserin inhibited 5-HT-activated TGF-b1-smad2/3 signaling in vitro and thereby depressed the MF conversion of PFs. Rats receiving DCD livers showed increased liver contents of 5-HT and HYP, impaired biliary function, up-regulation of fibrosis-related genes, and aggravated biliary fibrosis. However, these phenomena were alleviated by treatment with ketanserin. We concluded that the profibrotic activity of 5-HT occurred through the activation of TGF-b1 signaling and the 5-HT2A receptor. Thus, these data suggest that the 5-HT2A receptor may be a potential therapeutic target for ischemia-related biliary fibrosis after DCD liver transplantation. Liver Transpl 20:1317-1326, 2014. V C 2014 AASLD.Received March 30, 2014; accepted July 2, 2014.The worldwide organ shortage has led to the increased use of donation after cardiac death (DCD) livers. Because of the additional warm ischemia before preservation, DCD liver grafts are at higher risk for failure and bile duct injury. Currently, DCD liver grafts are the most common cause of nonanastomotic biliary strictures, which are characterized as biliary strictures and dilatation at any location in the biliary system of the transplanted liver.1,2 They are associated with an increased incidence of biliary sludge, recurrent Abbreviations: 5-HT, 5-hydroxytryptamine; 5-HT1K, 5-hydroxytryptamine and ketanserin; a-SMA, a-smooth muscle actin; ALP, alkaline phosphatase; BECs, biliary epithelial cells; DCD, donation after cardiac death; GGT, gamma-glutamyl transpeptidase; HSC, hepatic stellate cell; HYP, hydroxyproline; MF, myofibroblast; MMP2, matrix metalloproteinase 2; mRNA, messenger RNA; PF, portal fibroblast; PI, proliferation index; p-smad, phosphorylated drosophila mothers against decapentaplegic protein; RTqPCR, quantitative real-time reverse-transcr...

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5‐HT_2A receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis

Abstract: 5-HT2A receptor antagonists can reduce inflammation and the activation of HSCs in this cirrhotic model.

Cited by 40 publications

References 32 publications

Biology of portal hypertension

Biology of portal hypertension

Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats

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

Abstract: 5-HT2A receptor antagonists can reduce inflammation and the activation of HSCs in this cirrhotic model.

Cited by 40 publications

References 32 publications

Biology of portal hypertension

Biology of portal hypertension

Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats

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5‐HT_2A receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis