title: Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells.
abstract: 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.
authors.affiliation: Dept. of Gastroenterology, Univ. of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. ikeda-1im@h.u-tokyo.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Kayo
authors.initials: K
authors.lastname: Nagashima
authors.forename: Mikio
authors.initials: M
authors.lastname: Yanase
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tomiya
authors.forename: Masahiro
authors.initials: M
authors.lastname: Arai
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inoue
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tejima
authors.forename: Takako
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujiwara
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001769:Blood; D001905:Botulinum Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; C494828:Bax protein, rat; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C108830:Y 27632; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins