Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hepatology. 2012 Oct;56(4):1427-38. doi: 10.1002/hep.25780.
Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1-phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P 2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct-ligated livers. Furthermore, the increase of Rho kinase activity in bile duct-ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P 2-/- mice.
S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension.
探讨鞘氨醇 1-磷酸（S1P）是否通过 S1P 受体 2（S1P2）激活 Rho 来刺激肝星状细胞的收缩性，并增加分离灌注的大鼠肝脏中的门静脉压力。
通过静脉内输注 S1P2 拮抗剂 JTE-013（1mg/kg 体重），观察其对 4 周胆管结扎诱导的肝硬化大鼠门静脉压力的影响。同时，还观察了 S1P2 拮抗剂对对照组假手术大鼠门静脉压力和平均动脉压的影响。采用 Rho 激酶活性检测、S1P2 信使 RNA（mRNA）表达分析和 S1P2 蛋白免疫印迹实验，研究 S1P2 在门静脉高压发病机制中的作用及其与 Rho 激酶的关系。
静脉内输注 S1P2 拮抗剂可使肝硬化大鼠的门静脉压力降低 24%，而不影响平均动脉压。与假手术大鼠相比，胆管结扎大鼠的肝组织 Rho 激酶活性增强，而 S1P2 拮抗剂可降低胆管结扎大鼠肝组织中的 Rho 激酶活性。在胆管结扎大鼠和小鼠的肝脏以及培养的大鼠肝星状细胞中，S1P2 mRNA 表达增加，而 S1P1 和 S1P3 mRNA 表达无明显变化。S1P2LacZ/+ 小鼠的 S1P2 表达在胆管结扎肝脏中显著增加。此外，在野生型小鼠中，胆管结扎后 7 天即可观察到 Rho 激酶活性的增加，而 S1P2-/- 小鼠的增加程度较小。
S1P 可能通过 S1P2 激活 Rho 激酶在门静脉高压的发病机制中发挥重要作用。S1P2 拮抗剂有望成为治疗门静脉高压的一种新的治疗药物。
