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

Abstract

UNLABELLED:

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.

CONCLUSION:

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.

• Authors: Yuko Kageyama, Hitoshi Ikeda, Naoko Watanabe, Masakazu Nagamine, Yoshika Kusumoto, Mitsuru Yashiro, Yumiko Satoh, Tatsuo Shimosawa, Koji Shinozaki, Tomoaki Tomiya, Yukiko Inoue, Takako Nishikawa, Natsuko Ohtomo, Yasushi Tanoue, Hiromitsu Yokota, Takatoshi Koyama, Kazuhiro Ishimaru, Yasuo Okamoto, Yoh Takuwa, Kazuhiko Koike, Yutaka Yatomi
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 56 Issue 4 Pg. 1427-38 (Oct 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22505286 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• JTE 013
• Pyrazoles
• Pyridines
• Receptors, Lysosphingolipid
• rho-Associated Kinases

Topics

• Animals
• Bile Ducts (surgery)
• Cells, Cultured (drug effects)
• Disease Models, Animal
• Enzyme Activation (drug effects, genetics)
• Gene Expression Regulation
• Hemodynamics (drug effects, physiology)
• Hepatic Stellate Cells (drug effects, physiology)
• Hypertension, Portal (drug therapy, physiopathology)
• Immunoblotting
• Immunohistochemistry
• Infusions, Intravenous
• Ligation
• Male
• Mice
• Mice, Transgenic
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Receptors, Lysosphingolipid (antagonists & inhibitors, drug effects, genetics)
• Reference Values
• Sensitivity and Specificity
• rho-Associated Kinases (drug effects, metabolism)