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Originally published online as doi:10.2353/ajpath.2009.080261 on January 22, 2009

Published online before print January 22, 2009
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(American Journal of Pathology. 2009;174:881-890.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080261

Suppressive Effect of Orthovanadate on Hepatic Stellate Cell Activation and Liver Fibrosis in Rats

Yuji Nishikawa*, Naoto Ohi*, Akiko Yagisawa*, Yuko Doi{dagger}, Yohei Yamamoto*, Masayuki Yoshida*, Takuo Tokairin*, Toshiaki Yoshioka*, Yasufumi Omori* and Katsuhiko Enomoto*

From the Department of Pathology* and the Central Research Laboratory,{dagger} Akita University School of Medicine, Akita, Japan

Orthovanadate (OV), an inhibitor of protein tyrosine phosphatases, affects various biological processes in a cell-type-specific manner. In this study, we investigated the effect of OV on hepatic stellate cells (HSCs). When primary rat HSCs were cultured in the presence of 10% serum, they spontaneously lost characteristic stellate morphology, proliferated, and were transformed into an activated state with the formation of abundant stress fibers and increased expression of both {alpha}-smooth muscle actin and collagen type I mRNA. OV treatment inhibited proliferation and activation of HSCs and partially reversed the phenotype of activated HSCs. Among the signaling molecules investigated, phosphorylation of the Src protein at tyrosine 416 was the most striking in OV-treated HSCs. Treatment of cells with Src family inhibitors partially abrogated the effects of OV. Furthermore, transfection of v-Src into activated HSCs induced a stellate morphology similar to that in the quiescent state. We then examined whether OV could effectively suppress HSC activation in vivo after liver injury induced by either carbon tetrachloride or dimethylnitrosamine. OV significantly reduced the appearance of {alpha}-smooth muscle actin-positive cells and decreased collagen deposition, concomitant with an improvement in liver function. Our study showed for the first time that OV was able to suppress the activation of HSCs, possibly through the modulation of Src activity, and attenuated fibrosis after chronic liver injury.






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Copyright © 2009 by the American Society for Investigative Pathology.