ag-490 and Hypertension--Portal

Angiotensin II (AngII) activates via angiotensin-II-type-I receptor (AT1R) Janus-kinase-2 (JAK2)/Arhgef1 pathway and subsequently RHOA/Rho-kinase (ROCK), which induces experimental and probably human liver fibrosis. This study investigated the relationship of JAK2 to experimental and human portal hypertension.. The mRNA and protein levels of JAK2/ARHGEF1 signalling components were analysed in 49 human liver samples and correlated with clinical parameters of portal hypertension in these patients. Correspondingly, liver fibrosis (bile duct ligation (BDL), carbon tetrachloride (CCl. Hepatic transcription of JAK2/ARHGEF1 pathway components was upregulated in liver cirrhosis dependent on aetiology, severity and complications of human liver cirrhosis (Model for End-stage Liver disease (MELD) score, Child score as well as ascites, high-risk varices, spontaneous bacterial peritonitis). SM22. Hepatic JAK2/ARHGEF1/ROCK expression is associated with portal hypertension and decompensation in human cirrhosis. The deletion of Jak2 in myofibroblasts attenuated experimental fibrosis and acute inhibition of JAK2 decreased PP. Thus, JAK2 inhibitors, already in clinical use for other indications, might be a new approach to treat cirrhosis with portal hypertension.

Topics: Adult; Animals; Carbon Tetrachloride; Collagen; Enzyme Inhibitors; Female; Hepatic Stellate Cells; Humans; Hypertension, Portal; Janus Kinase 2; Ligation; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Middle Aged; Muscle Proteins; Myofibroblasts; Portal Pressure; Rats; Rats, Sprague-Dawley; Rho Guanine Nucleotide Exchange Factors; rho-Associated Kinases; rhoA GTP-Binding Protein; RNA, Messenger; Severity of Illness Index; Signal Transduction; Transcription, Genetic; Tyrphostins; Up-Regulation; Vascular Resistance; Young Adult

AG490, the specific inhibitor of JAK2/STAT3 signaling, has been shown to decrease portal pressure, splanchnic hyperdynamic circulation and liver fibrosis in cirrhotic rats. Nonselective betablockers such as propranolol are the only drugs recommended in the treatment of portal hypertension. The aim of this study was to explore the combinative effect of treatment with propranolol and AG490 on portal hypertension.. Rats induced by common bile duct ligation were treated with vehicle, AG490, propranolol, or AG490 + propranolol for 2 weeks. Hemodynamics parameters were assessed. Expressions of phospho-STAT3 protein and its down-regulated cytokines in splanchnic organs were detected by ELISA or western blot. Lipopolysaccharide binding protein (LBP) and IL-6 were assessed by ELISA or western blot. Characterization of liver and mesentery was performed by histological analyses.. Highly expressed phospho-STAT3 protein in cirrhotic rats could successfully be inhibited by AG490 or AG490 + propranolol treatments but not by propranolol alone. Both AG490 and propranolol significantly reduced portal pressure and hyperdynamic splanchnic circulation, and combination of AG490 and propranolol achieved an additive effect than with either drug alone. AG490, alone or in combination with propranolol, inhibited liver fibrosis, splenomegaly and splanchnic angiogenesis. Increased markers of bacterial translocation (LBP and IL6) were greatly reduced by propranolol but not by AG490.. The combination of propranolol and AG490 caused a greater improvement of portal hypertension and might therefore offer a potentially promising therapy in the portal hypertension treatment.

Topics: Acute-Phase Proteins; Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Bacterial Translocation; Carrier Proteins; Common Bile Duct; Disease Models, Animal; Drug Therapy, Combination; Hypertension, Portal; Interleukin-6; Intestinal Mucosa; Intestines; Ligation; Liver; Liver Cirrhosis, Biliary; Male; Membrane Glycoproteins; Neovascularization, Pathologic; Phosphorylation; Portal Pressure; Propranolol; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Splanchnic Circulation; Spleen; STAT3 Transcription Factor; Tyrphostins

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

Topics: Animals; Blotting, Western; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Hypertension, Portal; Immunohistochemistry; Janus Kinase 2; Liver Cirrhosis, Experimental; Male; Portal Pressure; Rats; Rats, Sprague-Dawley; Signal Transduction; Syndrome; Tyrphostins