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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis
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Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis

机译：继发性胆汁性肝硬化大鼠中的rho激酶激活介导了内皮一氧化氮合酶信号的缺陷

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摘要

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, I 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, I 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.
机译：在肝硬化中，内皮型一氧化氮合酶（eNOS）的下调被认为是肝内耐药性增加的原因。我们调查了Rho激酶激活是否是继发性胆汁性肝硬化中有缺陷的eNOS信号传导的分子机制之一。胆管结扎术（BDL）可诱发肝硬化。我们在静脉输注法舒地尔60、0.3、1或2 mg / kg /小时的盐水（对照组）期间测量了平均动脉压（MAP），门静脉压（PVP）和肝组织血流量（HTBF）。在BDL大鼠中，I和2 mg / kg /小时的法舒地尔与对照组相比PVP明显降低了20％，但对HTBF没有影响。响应2 mg / kg /小时法舒地尔，MAP显着降低。与对照组相比，在BDL大鼠的肝脏中，I和2 mg / kg /小时的法舒地尔显着抑制Rho激酶活性，并显着增加eNOS磷酸化。法舒地尔显着降低了丝氨酸/苏氨酸Akt / PKB（Akt）与Rho激酶的结合，并提高了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激酶激活并导致eNOS下调与门脉高压的发病机理密切相关;（2）Rho激酶可能与Akt相互作用，进而抑制Akt与eNOS的结合。

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