Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis.
OBJECTIVE
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.


DESIGN
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.


RESULTS
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/f mice lacking Jak2 developed less fibrosis and lower portal pressure (PP) than SM22Cre--Jak2f/f upon fibrosis induction. Myofibroblasts from SM22Cre+-Jak2f/f mice 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.


CONCLUSIONS
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.
['Klein|Sabine|S|', 'Rick|Johanna|J|', 'Lehmann|Jennifer|J|', 'Schierwagen|Robert|R|', 'Schierwagen|Irela Gretchen|IG|', 'Verbeke|Len|L|', 'Hittatiya|Kanishka|K|', 'Uschner|Frank Erhard|FE|', 'Manekeller|Steffen|S|', 'Strassburg|Christian P|CP|', 'Wagner|Kay-Uwe|KU|', 'Sayeski|Peter P|PP|', 'Wolf|Dominik|D|', 'Laleman|Wim|W|', 'Sauerbruch|Tilman|T|', 'Trebicka|Jonel|J|']
D000328:Adult D000818:Animals D002251:Carbon Tetrachloride D003094:Collagen D004791:Enzyme Inhibitors D005260:Female D055166:Hepatic Stellate Cells D006801:Humans D006975:Hypertension, Portal D053614:Janus Kinase 2 D008026:Ligation D008103:Liver Cirrhosis D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008840:Microfilament Proteins D008875:Middle Aged D009124:Muscle Proteins D058628:Myofibroblasts D017082:Portal Pressure D012333:RNA, Messenger D051381:Rats D017207:Rats, Sprague-Dawley D064067:Rho Guanine Nucleotide Exchange Factors D012720:Severity of Illness Index D015398:Signal Transduction D014158:Transcription, Genetic D020032:Tyrphostins D015854:Up-Regulation D014655:Vascular Resistance D055815:Young Adult D054460:rho-Associated Kinases D020742:rhoA GTP-Binding Protein
PORTAL HYPERTENSION FIBROSIS LIVER CIRRHOSIS