title: Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis.
abstract: 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 (CCl4)) was induced in floxed-Jak2 knock-out mice with SM22-promotor (SM22Cre+-Jak2f/f). Transcription and contraction of primary myofibroblasts from healthy and fibrotic mice and rats were analysed. In two different cirrhosis models (BDL, CCl4) in rats, the acute haemodynamic effect of the JAK2 inhibitor AG490 was assessed using microsphere technique and isolated liver perfusion experiments.
  
  
  
  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). SM22Cre+- Jak2f/fmice lacking Jak2 developed less fibrosis and lower portal pressure (PP) than SM22Cre--Jak2f/fupon fibrosis induction. Myofibroblasts from SM22Cre+-Jak2f/fmice expressed less collagen and profibrotic markers upon activation. AG490 relaxed activated hepatic stellate cells in vitro. In cirrhotic rats, AG490 decreased hepatic vascular resistance and consequently the PP in vivo and in situ.
  
  
  
  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.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rick
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Irela Gretchen
authors.initials: IG
authors.lastname: Schierwagen
authors.affiliation: Department of Liver and Biliopancreatic Disorders, University of Leuven, Leuven, Belgium.
authors.forename: Len
authors.initials: L
authors.lastname: Verbeke
authors.affiliation: Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Hittatiya
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Frank Erhard
authors.initials: FE
authors.lastname: Uschner
authors.affiliation: Department of General and Visceral Surgery, University of Bonn, Bonn, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Manekeller
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, College of Medicine, Gainesville, Florida, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Sayeski
authors.affiliation: Medical Clinic III, Oncology, Hematology and Rheumatology, University of Bonn, Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Department of Liver and Biliopancreatic Disorders, University of Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
mesh_terms: D000328:Adult; D000818:Animals; D002251:Carbon Tetrachloride; D003094:Collagen / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D055166:Hepatic Stellate Cells / Q000187:drug effects; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008026:Ligation; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D058628:Myofibroblasts / Q000502:physiology; D017082:Portal Pressure / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats / Q000502:physiology; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction; D014158:Transcription, Genetic; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation; D014655:Vascular Resistance / Q000187:drug effects; D055815:Young Adult; D054460:rho-Associated Kinases / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D064067:Rho Guanine Nucleotide Exchange Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C051615:transgelin; D003094:Collagen; D002251:Carbon Tetrachloride; D053614:Janus Kinase 2; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: FIBROSIS; LIVER CIRRHOSIS; PORTAL HYPERTENSION