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Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis
  1. Sabine Klein1,
  2. Johanna Rick1,
  3. Jennifer Lehmann1,
  4. Robert Schierwagen1,
  5. Irela Gretchen Schierwagen2,
  6. Len Verbeke3,
  7. Kanishka Hittatiya4,
  8. Frank Erhard Uschner1,
  9. Steffen Manekeller5,
  10. Christian P Strassburg1,
  11. Kay-Uwe Wagner6,
  12. Peter P Sayeski7,
  13. Dominik Wolf8,
  14. Wim Laleman3,
  15. Tilman Sauerbruch1,
  16. Jonel Trebicka1
  1. 1Department of Internal Medicine I, University of Bonn, Bonn, Germany
  2. 2Institute for Cell Biology, University of Bonn, Bonn, Germany
  3. 3Department of Liver and Biliopancreatic Disorders, University of Leuven, Leuven, Belgium
  4. 4Institute of Pathology, University of Bonn, Bonn, Germany
  5. 5Department of General and Visceral Surgery, University of Bonn, Bonn, Germany
  6. 6Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
  7. 7Department of Physiology and Functional Genomics, University of Florida, College of Medicine, Gainesville, Florida, USA
  8. 8Medical Clinic III, Oncology, Hematology and Rheumatology, University of Bonn, Bonn, Germany
  1. Correspondence to Professor Dr Jonel Trebicka, Department of Internal Medicine I, University of Bonn, Sigmund-Freud Str. 25, Bonn D-53105, Germany; jonel.trebicka{at}ukb.uni-bonn.de

Abstract

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.

  • PORTAL HYPERTENSION
  • LIVER CIRRHOSIS
  • FIBROSIS

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