title: Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction.
abstract: Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl4-caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl4-administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl4-induced liver injury. DHA also reduced CCl4-caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, China.
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, China.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, China.
authors.forename: Jiangjuan
authors.initials: J
authors.lastname: Shao
authors.affiliation: Class AP, Grade 11, Nanjing No. 1 High School, China.
authors.forename: Shunyu
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, China.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D037621:Artemisinins / Q000494:pharmacology*; D002251:Carbon Tetrachloride; D016923:Cell Death / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006975:Hypertension, Portal / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011169:Portal Vein / Q000187:drug effects; D011282:Pregnenediones / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D037621:Artemisinins; D002251:Carbon Tetrachloride; D002635:Chenodeoxycholic Acid; D011282:Pregnenediones; D020011:Protective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid; C039060:artenimol; C023617:pregna-4,17-diene-3,16-dione
keywords: contraction; dihydroartemisinin; farnesoid X receptor; hepatic stellate cell; portal hypertension