Anegawa Go, Kawanaka Hirofumi, Yoshida Daisuke, Konishi Kozo, Yamaguchi Shohei, Kinjo Nao, Taketomi Akinobu, Hashizume Makoto, Shimokawa Hiroaki, Maehara Yoshihiko
Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Hepatology. 2008 Mar;47(3):966-77. doi: 10.1002/hep.22089.
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.
在肝硬化中，内皮型一氧化氮合酶（eNOS）的下调被认为是肝内阻力增加的一个原因。我们研究了Rho激酶激活是否是继发性胆汁性肝硬化中eNOS信号传导缺陷所涉及的分子机制之一。通过胆管结扎（BDL）诱导肝硬化。在静脉输注生理盐水（对照）、0.3、1或2mg/kg/小时法舒地尔60分钟期间，我们测量了平均动脉压（MAP）、门静脉压（PVP）和肝组织血流量（HTBF）。在BDL大鼠中，与对照组相比，1和2mg/kg/小时法舒地尔使PVP显著降低了20%，但对HTBF没有影响。2mg/kg/小时法舒地尔使MAP显著降低。与对照组相比，在BDL大鼠的肝脏中，1和2mg/kg/小时法舒地尔显著抑制了Rho激酶活性，并显著增加了eNOS磷酸化。法舒地尔显著降低了丝氨酸/苏氨酸蛋白激酶B（Akt）与Rho激酶的结合，并增加了Akt与eNOS的结合。这些结果表明，在继发性胆汁性肝硬化中，（1）Rho激酶激活导致eNOS下调在门静脉高压的发病机制中起重要作用，（2）Rho激酶可能与Akt相互作用，随后抑制Akt与eNOS的结合。
