title: Dihydroartemisinin restricts hepatic stellate cell contraction via an FXR-S1PR2-dependent mechanism.
abstract: Hepatic stellate cells (HSCs) are universally acknowledged to play a stimulative role in the pathogenesis of hepatic fibrosis and portal hypertension. HSCs when activated in response to liver injury are characterized with many changes, with HSC contraction being the most common cause of portal hypertension. Previous studies have shown that dihydroartemisinine (DHA) is a potential antifibrotic natural product by inducing HSC apoptosis, whereas the role of DHA in regulating HSC contraction and the mechanisms involved remain a riddle. Recent studies have emphasized on the importance of farnesoid X receptor (FXR) and sphingosine-1-phosphate receptor 2 (S1PR2) in controlling cell contractility. This study showed that DHA strongly induced the mRNA and protein expression of FXR in LX-2 cells in a dose- and time-dependent manner and inhibited HSC activation, implying a conceivable impact of DHA on HSC contraction. The gel contraction assays and fluorescence staining of actin cytoskeleton verified that DHA dose-dependently limited contraction of collagen lattices and reorganization of actin stress fibers in LX-2 cells. DHA also decreased the phosphorylation of myosin light chain that is responsible for the contractile force of HSCs. Furthermore, gain- or loss-of-function analyses exhibited a FXR- and S1PR2-dependent mechanism of inhibiting HSC contraction by DHA, and DHA decreased S1PR2 expression by modulating FXR activation. Subsequent work revealed that inhibition of both Ca(2+) -dependent and Ca(2+) -sensitization signaling transductions contributed to DHA-induced HSC relaxation. In summary, these findings suggest that DHA could restrict HSC contraction through modulating FXR/S1PR2 pathway-mediated Ca(2+) -dependent and Ca(2+) -sensitization signaling. Our discoveries make DHA a potential candidate for portal hypertension. © 2016 IUBMB Life 68(5):376-387, 2016.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
authors.forename: Jiangjuan
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D037621:Artemisinins / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D037621:Artemisinins; D018160:Receptors, Cytoplasmic and Nuclear; D049349:Receptors, Lysosphingolipid; D000099150:Receptor, Farnesoid X-Activated; C039060:artenimol
keywords: FXR; S1PR2; contraction; dihydroartemisinin; hepatic stellate cell; portal hypertension