Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Departments of General Surgery, TangDu Hospital, Xi'an, China.
Dong
D
Wang
Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Qin
Q
Wang
Departments of General Surgery, TangDu Hospital, Xi'an, China.
Jikai
J
Yin
Departments of General Surgery, TangDu Hospital, Xi'an, China.
Rui
R
Dong
Departments of General Surgery, TangDu Hospital, Xi'an, China.
Qing
Q
Wang
Departments of General Surgery, TangDu Hospital, Xi'an, China.
Xilin
X
Du
Departments of General Surgery, TangDu Hospital, Xi'an, China.
Jianguo
J
Lu
D000209:Acute-Phase Proteins / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D018988:Bacterial Translocation / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D003135:Common Bile Duct / Q000601:surgery; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D017082:Portal Pressure / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013152:Splanchnic Circulation / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002352:Carrier Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D011433:Propranolol; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; D000099231:Lipopolysaccharide-Binding Protein; C494088:Stat3 protein, rat; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
AG490; JAK2/STAT3 signaling; cirrhosis; portal hypertension; propranolol