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1 Department of Gastroenterology, University of Tokyo, Tokyo, Japan
2 Department of Infectious Disease, University of Tokyo, Tokyo, Japan
3 Third Department of Internal Medicine, Saitama Medical School, Saitama, Japan
* To whom correspondence should be addressed. E-mail: ikeda-1im{at}h.u-tokyo.ac.jp.
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 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 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 Rho/Rho kinase pathway causes HSC apoptosis. On the other hand, lysophosphatidic acid, which stimulates Rho/Rho kinase pathway, decreased histone-associated DNA fragmentation in HSCs. The inhibition of Rho/Rho kinase pathway did not affect p53, Bcl-2 or Bax levels in HSCs. Thus, we concluded that Rho/Rho kinase pathway may play a role in regulation of HSC survival.
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