title: Smad2 increases the apoptosis of activated human hepatic stellate cells induced by TRAIL.
abstract: The activation of hepatic stellate cells (HSCs) plays a critical role in the development of liver fibrosis. The induction of apoptosis in activated HSCs during the recovery phase of hepatic fibrosis represents a potential anti-fibrotic therapy. We have previously shown that Smad2 protects against hepatic fibrogenesis; however, the role of Smad2 in the regulation of activated HSC apoptosis remains unknown. We hypothesized that Smad2 regulates the apoptosis of activated HSCs, leading to the resolution of liver fibrosis. To test this hypothesis, the livers of rats were harvested at 0 and 4 weeks after hepatic fibrosis was established by CCl4 injection. Furthermore, TGF-β1-activated HSCs were treated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following the silencing or overexpression of Smad2. Both the phosphorylation of Smad2 and TRAIL were detected in fibrotic liver tissues. The results of TUNEL and α-SMA double-staining showed an increase in the apoptosis of activated HSCs during the spontaneous recovery phase. The knockdown of Smad2 reduced TRAIL-induced apoptosis in TGF-β1-activated human LX-2 cells and resulted in an increased expression of α-SMA and collagen I (Col. I). In contrast, the overexpression of Smad2 increased TRAIL-induced HSC apoptosis and reduced the expression of α-SMA and Col. I. The mechanisms underlying these findings were associated with the Smad2-mediated down-regulation of X-linked inhibitor of apoptosis protein (XIAP), resulting in enhanced caspase-3 activity and apoptosis. In conclusion, Smad2 enhances TRAIL-induced apoptosis in activated HSCs, which facilitates the resolution of hepatic fibrosis.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), China.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), China. Electronic address: zhanglei_xu@sina.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002251:Carbon Tetrachloride; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D000199:Actins; D002251:Carbon Tetrachloride; D053148:Caspase 3; D024042:Collagen Type I; D012333:RNA, Messenger; D051899:Smad2 Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; D053773:Transforming Growth Factor beta1; D051636:X-Linked Inhibitor of Apoptosis Protein; C497782:SMAD2 protein, human; C496866:XIAP protein, human; C498862:Acta2 protein, rat
keywords: Apoptosis; Hepatic fibrosis; Smad2; TGF-β1; TRAIL; XIAP