Rho inhibitor prevents ischemia-reperfusion injury in rat steatotic liver
Rho inhibitor prevents ischemia-reperfusion injury in rat steatotic liver
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DOI：
10.1016/j.jhep.2011.04.029
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发表时间：
2012-01-01
影响因子：
25.7
通讯作者：
Ohdan, Hideki
中科院分区：
文献类型：
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作者：
Kuroda, Shintaro;Tashiro, Hirotaka;Ohdan, Hideki
背景和目标：肝星状细胞被认为在调节肝内血管阻力中发挥作用，这是基于它们通过Rho信号传导收缩的能力。我们研究了Rho激酶抑制剂对脂肪肝缺血再灌注损伤的影响。方法：脂肪肝，由胆碱缺乏的饮食诱导大鼠，进行缺血再灌注损伤。分析从脂肪变性肝脏分离的肝星状细胞的收缩性和Rho信号传导活性。结果：与正常肝相比，脂肪肝肝星状细胞收缩力增强，Rho激酶2表达上调。此外，内皮素-1显着增强的收缩性和肌球蛋白轻链和cofilin的磷酸化水平在肝星状细胞分离脂肪肝。一种特异性Rho激酶抑制剂法舒地尔可显著抑制心肌收缩力，并降低肌球蛋白轻链和cofilin的磷酸化水平。在脂肪肝大鼠IR后，血清内皮素-1水平显著升高，而法舒地尔显著降低血清内皮素-1水平。脂肪肝大鼠表现出显着增加门静脉灌注压缺血再灌注后，存活率显着下降;法舒地尔治疗显着降低这些effectiveness.Conclusions：激活Rho/Rho激酶信号在肝星状细胞分离脂肪肝与缺血再灌注损伤的易感性增加。Rho激酶抑制剂可减弱脂肪肝大鼠肝星状细胞的活化，改善缺血再灌注损伤。(C)2011年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Hepatic stellate cells are thought to play a role in modulating intrahepatic vascular resistance based on their capacity to contract via Rho signaling. We investigated the effect of a Rho-kinase inhibitor on ischemia-reperfusion injury in the steatotic liver.Methods: Steatotic livers, induced by a choline-deficient diet in rats, were subjected to ischemia-reperfusion injury. Hepatic stellate cells isolated from steatotic livers were analyzed for contractility and Rho signaling activity. The portal pressure of the perfused rat liver and the survival rate after ischemia-reperfusion were also investigated.Results: Hepatic stellate cells from steatotic livers showed increased contractility and upregulation of Rho-kinase 2 compared with those from normal livers. Furthermore, endothelin-1 significantly enhanced the contractility and phosphorylation level of myosin light chain and cofilin in hepatic stellate cells isolated from steatotic livers. A specific Rho-kinase inhibitor, fasudil, significantly suppressed the contractility and decreased the phosphorylation levels of myosin light chain and cofilin. Serum levels of endothelin-1 were markedly increased after IR in rats with steatotic livers, whereas fasudil significantly decreased endothelin-1 serum levels. Rats with steatotic livers showed a significant increase in portal perfusion pressure after ischemia-reperfusion and a significant decrease in survival rate; fasudil treatment significantly reduced these effects.Conclusions: Activation of Rho/Rho-kinase signaling in hepatic stellate cells isolated from steatotic livers is associated with an increased susceptibility to ischemia-reperfusion injury. A Rho-kinase inhibitor attenuated the activation of hepatic stellate cells isolated from steatotic livers and improved ischemia-reperfusion injury in steatotic rats. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.