title: Depletion of β-arrestin2 in hepatic stellate cells reduces cell proliferation via ERK pathway.
abstract: β-Arrestins are multifunctional adaptor proteins. Recently, some new roles of β-arrestins in regulating intracellular signaling networks have been discovered, which regulate cell growth, proliferation, and apoptosis. Though, the role of β-arrestins expression in the pathology of hepatic fibrosis remains unclear. In this study, the possible relationship between the expression of β-arrestins with the experimental hepatic fibrosis and the proliferation of hepatic stellate cells (HSCs) were investigated. Porcine serum induced liver fibrosis was established in this study. At five time points, the dynamic expression of β-arrestin1, β-arrestin2, and α-smooth muscle actin (α-SMA) in rat liver tissues, was measured by immunohistochemical staining, double immunofluorescent staining, and Western blotting. This study showed that aggravation of hepatic fibrosis with gradually increasing expression of β-arrestin2 in the hepatic tissues, but not β-arrestin1. Further, as hepatic fibrosis worsens, β-arrestin2-expressing activated HSCs accounts for an increasingly larger percentage of all activated HSCs. And the expression of β-arrestin2 had a significant positive correlation with the expression of α-SMA, an activated HSCs marker. In vitro studies, the dynamic expression of β-arrestin1 and β-arrestin2 in platelet derived growth factor-BB (PDGF-BB) stimulated HSCs was assessed by Western blotting. The expression of β-arrestin2 was remarkably increased in PDGF-BB stimulated HSCs. Furthermore, the small interfering RNA (siRNA) technique was used to explore the effect of β-arrestins on the proliferation of HSCs and the activation of ERK1/2. Transfection of siRNA targeting β-arrestin2 mRNA (siβ-arrestin2) into HSCs led to a 68% and 70% reduction of β-arrestin2 mRNA and protein expression, respectively. siβ-arrestin2 abolished the effect of PDGF-BB on the proliferation of HSCs. In addition, siβ-arrestin2 exerted the inhibition of the activation of ERK1/2 in HSCs. The present study provided strong evidence for the participation of the β-arrestin2 in the pathogenesis of hepatic fibrosis. The β-arrestin2 depletion diminishes HSCs ERK1/2 signaling and proliferation stimulated by PDGF-BB. Selective targeting of β-arrestin2 inhibitors to HSCs might present as a novel strategy for the treatment of hepatic fibrosis.
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Engineering Technology Research Center of Anti-inflammatory and Immunodrugs in Anhui Province, Hefei, Anhui Province 230032, China.
authors.forename: Wu-Yi
authors.initials: WY
authors.lastname: Sun
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Hu
authors.forename: Qing-Tong
authors.initials: QT
authors.lastname: Wang
authors.forename: Hua-Xun
authors.initials: HX
authors.lastname: Wu
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077214:Becaplermin; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D034421:Sus scrofa; D013997:Time Factors; D000071557:beta-Arrestins
chemical_list: D000199:Actins; D019390:Arrestins; D000077214:Becaplermin; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D000071557:beta-Arrestins; C498862:Acta2 protein, rat