title: Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis.
abstract: Elevated tissue inhibitor of metalloproteinase 1 (TIMP-1) expression contributes to excess production of extracellular matrix in liver fibrosis. Herein, we constructed a recombinant adeno-associated virus (rAAV) carrying siRNA of the TIMP-1 gene (rAAV/siRNA-TIMP-1) and investigated its effects on liver fibrosis in rats. Two models of rat liver fibrosis, the carbon tetrachloride and bile duct ligation models, were treated with rAAV/siRNA-TIMP-1. In the carbon tetrachloride model, rAAV/siRNA-TIMP-1 administration attenuated fibrosis severity, as determined by histologic analysis of hepatic collagen accumulation, hydroxyproline content, and concentrations of types I and III collagen in livers and sera. Levels of mRNA and active matrix metalloproteinase (MMP) 13 were elevated, whereas levels of mRNA and active MMP-2 were decreased. Moreover, a marked decrease was noted in the expression of α-smooth muscle actin, a biomarker of activated hepatic stellate cells (HSCs), and transforming growth factor-β1, critical for the development of liver fibrosis. Similarly, rAAV/siRNA-TIMP-1 treatment significantly alleviated bile duct ligation-induced liver fibrosis. Furthermore, this treatment dramatically suppressed TIMP-1 expression in HSCs from both model rats. These data indicate that the administration of rAAV/siRNA-TIMP-1 attenuated liver fibrosis by directly elevating the function of MMP-13 and diminishing activated HSCs. It also resulted in indirect decreased expression of type I collagen, MMP-2, and transforming growth factor-β1. In conclusion, rAAV/siRNA-TIMP-1 may be an effective antifibrotic gene therapy agent.
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cong
authors.forename: Tianhui
authors.initials: T
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Xu
authors.initials: X
authors.lastname: Fan
authors.forename: Aiting
authors.initials: A
authors.lastname: Yang
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Bai
authors.forename: Zhen
authors.initials: Z
authors.lastname: Peng
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Tong
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Cong
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Tang
authors.forename: Baoen
authors.initials: B
authors.lastname: Wang
authors.forename: Jidong
authors.initials: J
authors.lastname: Jia
authors.forename: Hong
authors.initials: H
authors.lastname: You
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D002251:Carbon Tetrachloride; D003094:Collagen / Q000378:metabolism; D000229:Dependovirus / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000201:enzymology / Q000473:pathology; D008026:Ligation; D008103:Liver Cirrhosis / Q000235:genetics* / Q000628:therapy*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011995:Recombination, Genetic / Q000235:genetics*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000199:Actins; D002251:Carbon Tetrachloride; D003094:Collagen; D049452:Green Fluorescent Proteins; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C485184:enhanced green fluorescent protein; C498862:Acta2 protein, rat