Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents

作者：Kageyama Yuko; Ikeda Hitoshi^*; Watanabe Naoko; Nagamine Masakazu; Kusumoto Yoshika; Yashiro Mitsuru; Satoh Yumiko; Shimosawa Tatsuo; Shinozaki Koji; Tomiya Tomoaki; Inoue Yukiko; Nishikawa Takako; Ohtomo Natsuko; Tanoue Yasushi; Yokota Hiromitsu; Koyama Takatoshi; Ishimaru Kazuhiro; Okamoto Yasuo; Takuwa Yoh; Koike Kazuhiko; Yatomi Yutaka

来源：Hepatology, 2012, 56(4): 1427-1438.

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 (S1P2). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P2 antagonism on portal hypertension was examined. Intravenous infusion of the S1P2 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 S1P2 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 S1P2 antagonist. S1P2 messenger RNA (mRNA) expression, but not S1P1 or S1P3, was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P2 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. Conclusion: S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P2. The S1P2 antagonist merits consideration as a novel therapeutic agent for portal hypertension. (HEPATOLOGY 2012)

• 出版日期2012-10