Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
J Hepatol. 2012 Jan;56(1):146-52. doi: 10.1016/j.jhep.2011.04.029. Epub 2011 Jul 12.
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.
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.
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.
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.
肝星状细胞（HSCs）通过 Rho 信号通路收缩，被认为在调节肝内血管阻力方面发挥作用。我们研究了 Rho 激酶抑制剂对肝脂肪变性肝脏再灌注损伤的影响。
采用胆碱缺乏饮食诱导大鼠肝脂肪变性，建立肝脂肪变性肝脏再灌注损伤模型。分析肝脂肪变性大鼠来源的 HSCs 的收缩性和 Rho 信号活性。检测大鼠肝脏门静脉压力和再灌注后大鼠的存活率。
与正常肝脏来源的 HSCs 相比，肝脂肪变性大鼠来源的 HSCs 收缩性增加，Rho 激酶 2 表达上调。此外，内皮素-1 显著增强肝脂肪变性大鼠来源的 HSCs 的收缩性，并增加肌球蛋白轻链和丝切蛋白磷酸化水平。特异性 Rho 激酶抑制剂 fasudil 显著抑制 HSCs 的收缩性，并降低肌球蛋白轻链和丝切蛋白磷酸化水平。肝脂肪变性大鼠再灌注后血清内皮素-1 水平显著升高，fasudil 显著降低内皮素-1 水平。肝脂肪变性大鼠再灌注后门静脉灌注压显著升高，存活率显著降低；fasudil 治疗可显著降低这些作用。
肝脂肪变性大鼠来源的 HSCs 中 Rho/Rho 激酶信号的激活与再灌注损伤易感性增加有关。Rho 激酶抑制剂可抑制肝脂肪变性大鼠来源的 HSCs 的激活，改善肝脂肪变性大鼠的再灌注损伤。
