Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats.

Abstract

BACKGROUND AND AIMS:

JAK2/STAT3 signalling promotes fibrosis, angiogenesis and inflammation in many diseases; however, the role of this pathway in portal hypertension remains obscure. This study aimed to explore the function of JAK2/STAT3 signalling in portal hypertension and estimate the potential therapeutic effect of treatment with the specific inhibitor AG490.

METHODS:

Rats induced by partial portal vein ligation and common bile duct ligation were treated with AG490 for two weeks. Haemodynamic parameters were assessed. The levels of phospho-STAT3 protein and related cytokines were detected by western blotting of splanchnic organs. Liver, spleen and intestine characterization was performed using histological analyses. Peripheral blood cell counts were also detected.

RESULTS:

High levels of phospho-STAT3 protein were detected in portal hypertensive rats. AG490 effectively inhibited JAK2/STAT3 signalling and its downstream cytokines and provided protective effects by decreasing splanchnic neovascularization and inflammation and by attenuating portal pressure and hyperdynamic splanchnic circulation. In cirrhosis rats, AG490 inhibited intrahepatic fibrosis, angiogenesis and inflammation. AG490 improved the peripheral blood cell counts and the splenomegaly observed in these rats.

CONCLUSIONS:

JAK2/STAT3 signalling is essential in portal hypertension, and targeting JAK2/STAT3 may be a promising therapy to treat this condition.

• Authors: Dong Wang, Jikai Yin, Rui Dong, Jian Zhao, Qing Wang, Nan Wang, Shouli Wang, Xilin Du, Jianguo Lu
• Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver (Dig Liver Dis) Vol. 47 Issue 4 Pg. 315-23 (Apr 2015) ISSN: 1878-3562 [Electronic] Netherlands
• PMID: 25637451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• Jak2 protein, rat
• Janus Kinase 2

Topics

• Animals
• Blotting, Western
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Hypertension, Portal (drug therapy, enzymology, physiopathology)
• Immunohistochemistry
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Liver Cirrhosis, Experimental (drug therapy, enzymology, physiopathology)
• Male
• Portal Pressure
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Syndrome
• Tyrphostins (pharmacology)