1. Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis.
- Author
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Cong M, Liu T, Wang P, Fan X, Yang A, Bai Y, Peng Z, Wu P, Tong X, Chen J, Li H, Cong R, Tang S, Wang B, Jia J, and You H
- Subjects
- Actins metabolism, Animals, Bile Ducts pathology, Carbon Tetrachloride, Collagen metabolism, Disease Models, Animal, Enzyme Activation, Green Fluorescent Proteins metabolism, Hepatic Stellate Cells enzymology, Hepatic Stellate Cells pathology, Ligation, Male, Matrix Metalloproteinase 13 metabolism, Matrix Metalloproteinase 2 metabolism, Rats, Rats, Wistar, Transforming Growth Factor beta1 metabolism, Up-Regulation, Dependovirus metabolism, Liver Cirrhosis genetics, Liver Cirrhosis therapy, RNA, Small Interfering metabolism, Recombination, Genetic genetics, Tissue Inhibitor of Metalloproteinase-1 genetics, Tissue Inhibitor of Metalloproteinase-1 therapeutic use
- 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., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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