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Am J Physiol Gastrointest Liver Physiol 285: G880-G886, 2003. First published June 26, 2003; doi:10.1152/ajpgi.00039.2003
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LIVER AND BILIARY TRACT

Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells

Hitoshi Ikeda,1 Kayo Nagashima,1 Mikio Yanase,1 Tomoaki Tomiya,1 Masahiro Arai,1 Yukiko Inoue,1 Kazuaki Tejima,1 Takako Nishikawa,1 Masao Omata,1 Satoshi Kimura,2 and Kenji Fujiwara3

Departments of1Gastroenterology and 2Infectious Disease, University of Tokyo, 113-8655 Tokyo; and 3Third Department of Internal Medicine, Saitama Medical School, 350-0495 Saitama, Japan

Submitted 22 January 2003 ; accepted in final form 20 June 2003

Hepatic stellate cells (HSCs) play a central role in the development of hepatic fibrosis. Recent evidence has revealed that HSCs also play a role in its resolution, where HSC apoptosis was determined. Moreover, induction of HSC apoptosis caused a reduction of experimental hepatic fibrosis in rats. Thus knowing the mechanism of HSC apoptosis might be important to clarify the pathophysiology and establish the therapeutic strategy for hepatic fibrosis. In HSCs, Rho and Rho kinase are known to regulate contraction, migration, and proliferation with modulation of cell morphology. Controversy exists as to the participation of Rho and Rho kinase on cell survival, and little is known regarding this matter in HSCs. In this study, we directed our focus on the role of the Rho pathway in the regulation of HSC survival. C3, an inhibitor of Rho, increased histone-associated DNA fragmentation and caspase 3 activity with enhanced condensation of nuclear chromatin in rat cultured HSCs. Moreover, Y-27632, an inhibitor of Rho kinase, had the same effects, suggesting that inhibition of the Rho/Rho kinase pathway causes HSC apoptosis. On the other hand, lysophosphatidic acid, which stimulates the Rho/Rho kinase pathway, decreased histone-associated DNA fragmentation in HSCs. Inhibition of the Rho/Rho kinase pathway did not affect p53, Bcl-2, or Bax levels in HSCs. Thus we concluded that the Rho/Rho kinase pathway may play a role in the regulation of HSC survival.

lysophosphatidic acid; C3 exoenzyme; Y-27632


Address for reprint requests and other correspondence: H. Ikeda, Dept. of Gastroenterology, Univ. of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (E-mail: ikeda-1im{at}h.u-tokyo.ac.jp).




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