Dong Wang1, Jikai Yin1, Rui Dong1, Jian Zhao2, Qing Wang1, Nan Wang1, Shouli Wang3, Xilin Du4, Jianguo Lu5. 1. Department of General Surgery, TangDu Hospital, Fourth Military Medical University, Xi'an, China. 2. Department of Orthopedics, TangDu Hospital, Fourth Military Medical University, Xi'an, China. 3. Laboratory of General Surgery Department, TangDu Hospital, Fourth Military Medical University, Xi'an, China. 4. Department of General Surgery, TangDu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: dxlin0705@163.com. 5. Department of General Surgery, TangDu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: lujguo1963@163.com.
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.
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 hypertensiverats. 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 cirrhosisrats, 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: Christian Liedtke; Yulia A Nevzorova; Tom Luedde; Henning Zimmermann; Daniela Kroy; Pavel Strnad; Marie-Luise Berres; Jürgen Bernhagen; Frank Tacke; Jacob Nattermann; Ulrich Spengler; Tilman Sauerbruch; Alexander Wree; Zeinab Abdullah; René H Tolba; Jonel Trebicka; Twan Lammers; Christian Trautwein; Ralf Weiskirchen Journal: Front Med (Lausanne) Date: 2022-01-11