Defective endothelial nitric oxide synthase signaling is mediated by Rho-kinase activation in rats with secondary biliary cirrhosis

Go Anegawa, Hirofumi Kawanaka, Daisuke Yoshida, Kozo Konishi, Shohei Yamaguchi, Nao Kinjo, Akinobu Taketomi, Makoto Hashizume, Hiroaki Shimokawa, Yoshihiko Maehara

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Abstract

In liver cirrhosis, down-regulation of endothelial nitric oxide synthase (eNOS) has been implicated as a cause of increased intrahepatic resistance. We investigated whether Rho-kinase activation is one of the molecular mechanisms involved in defective eNOS signaling in secondary biliary cirrhosis. Liver cirrhosis was induced by bile duct ligation (BDL). We measured mean arterial pressure (MAP), portal venous pressure (PVP), and hepatic tissue blood flow (HTBF) during intravenous infusion of saline (control), 0.3, 1, or 2 mg/kg/hour fasudil for 60 minutes. In BDL rats, 1 and 2 mg/kg/hour fasudil significantly reduced PVP by 20% compared with controls but had no effect on HTBF. MAP was significantly reduced in response to 2 mg/kg/hour fasudil. In the livers of BDL rats, 1 and 2 mg/kg/hour fasudil significantly suppressed Rho-kinase activity and significantly increased eNOS phosphorylation, compared with controls. Fasudil significantly reduced the binding of serine/threonine Akt/PKB (Akt) to Rho-kinase and increased the binding of Akt to eNOS. These results show in secondary biliary cirrhosis that (1) Rho-kinase activation with resultant eNOS down-regulation is substantially involved in the pathogenesis of portal hypertension and (2) Rho-kinase might interact with Akt and subsequently inhibit the binding of Akt to eNOS.

Original languageEnglish
Pages (from-to)966-977
Number of pages12
JournalHepatology
Volume47
Issue number3
DOIs
Publication statusPublished - Mar 2008

All Science Journal Classification (ASJC) codes

  • Hepatology

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    Anegawa, G., Kawanaka, H., Yoshida, D., Konishi, K., Yamaguchi, S., Kinjo, N., Taketomi, A., Hashizume, M., Shimokawa, H., & Maehara, Y. (2008). Defective endothelial nitric oxide synthase signaling is mediated by Rho-kinase activation in rats with secondary biliary cirrhosis. Hepatology, 47(3), 966-977. https://doi.org/10.1002/hep.22089