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Published on: December 5, 2017
Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary
Go Anegawa1, Hirofumi Kawanaka, Daisuke Yoshida
1Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. gottin@surg2.med.kyushu-u.ac.jp
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.
Insights
In liver cirrhosis, Rho-kinase activation contributes to portal hypertension by impairing endothelial nitric oxide synthase (eNOS) signaling. Inhibiting Rho-kinase may restore eNOS function and reduce elevated portal pressure.
Area of Science:
- Hepatology
- Molecular Biology
- Cardiovascular Physiology
Background:
- Endothelial nitric oxide synthase (eNOS) down-regulation is linked to increased intrahepatic resistance in liver cirrhosis.
- The role of Rho-kinase activation in defective eNOS signaling in secondary biliary cirrhosis requires investigation.
Purpose of the Study:
- To investigate the involvement of Rho-kinase activation in impaired eNOS signaling in secondary biliary cirrhosis.
- To determine the effect of Rho-kinase inhibition on portal pressure and eNOS activity in a rat model of cirrhosis.
Main Methods:
- Secondary biliary cirrhosis was induced in rats via bile duct ligation (BDL).
- Rats received intravenous infusions of fasudil (a Rho-kinase inhibitor) at varying doses.
- Measurements included mean arterial pressure (MAP), portal venous pressure (PVP), hepatic tissue blood flow (HTBF), Rho-kinase activity, and eNOS phosphorylation.
Main Results:
- Fasudil administration significantly reduced portal venous pressure (PVP) in BDL rats.
- Rho-kinase activity was suppressed, and eNOS phosphorylation was increased by fasudil.
- Fasudil altered the interaction between Akt and Rho-kinase, and between Akt and eNOS.
Conclusions:
- Rho-kinase activation is a key factor in the pathogenesis of portal hypertension in secondary biliary cirrhosis, leading to eNOS down-regulation.
- Rho-kinase may inhibit eNOS function by interfering with Akt binding, suggesting potential therapeutic targets.
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