BACKGROUND/AIMS: In the fibrotic response to liver injury, hepatic stellate cells are activated, leading to the myofibroblastic cell shape, with actin cytoskeletal reorganization and increased extracellular matrix production. The reorganization of actin cytoskeleton suggests that the small GTP binding protein Rho might modulate the process of this myofibroblastic change. The aim of this study was to investigate the role of Rho in the phenotypic changes of hepatic stellate cells. METHODS: The phenotypic changes were investigated by the overexpression of Rho regulator, Rho GDI or dominant negative mutant of Rho in mouse hepatic stellate cell line, GRX cells. In activated rat hepatic stellate cells, the effects of microinjection of Botulinus toxin C3, which is the specific inhibitor for Rho, were analyzed. Furthermore, the effect of C3 on the type I collagen accumulation in hepatic stellate cells was investigated. RESULTS: Overexpression of Rho GDI or the dominant negative mutant of Rho caused the shrinkage cell shape and suppressed stress fiber formation. Microinjection of toxin C3 caused a markedly distorted cell shape and the disappearance of stress fibers in rat stellate cells. In addition, C3 strongly suppressed collagen accumulation in activated stellate cells. CONCLUSIONS: These results suggest that Rho regulates the actin cytoskeletal reorganization, and may be implicated in the collagen accumulation in activated stellate cells. These findings provide evidence for the role of Rho in the myofibroblastic phenotype in hepatic stellate cells.
BACKGROUND/AIMS: In the fibrotic response to liver injury, hepatic stellate cells are activated, leading to the myofibroblastic cell shape, with actin cytoskeletal reorganization and increased extracellular matrix production. The reorganization of actin cytoskeleton suggests that the small GTP binding protein Rho might modulate the process of this myofibroblastic change. The aim of this study was to investigate the role of Rho in the phenotypic changes of hepatic stellate cells. METHODS: The phenotypic changes were investigated by the overexpression of Rho regulator, Rho GDI or dominant negative mutant of Rho in mouse hepatic stellate cell line, GRX cells. In activated rat hepatic stellate cells, the effects of microinjection of Botulinus toxin C3, which is the specific inhibitor for Rho, were analyzed. Furthermore, the effect of C3 on the type I collagen accumulation in hepatic stellate cells was investigated. RESULTS: Overexpression of Rho GDI or the dominant negative mutant of Rho caused the shrinkage cell shape and suppressed stress fiber formation. Microinjection of toxin C3 caused a markedly distorted cell shape and the disappearance of stress fibers in rat stellate cells. In addition, C3 strongly suppressed collagen accumulation in activated stellate cells. CONCLUSIONS: These results suggest that Rho regulates the actin cytoskeletal reorganization, and may be implicated in the collagen accumulation in activated stellate cells. These findings provide evidence for the role of Rho in the myofibroblastic phenotype in hepatic stellate cells.
Authors: Andrew I Su; Luca G Guidotti; John Paul Pezacki; Francis V Chisari; Peter G Schultz Journal: Proc Natl Acad Sci U S A Date: 2002-08-12 Impact factor: 11.205
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