Sabine Klein1, Johanna Rick1, Jennifer Lehmann1, Robert Schierwagen1, Irela Gretchen Schierwagen2, Len Verbeke3, Kanishka Hittatiya4, Frank Erhard Uschner1, Steffen Manekeller5, Christian P Strassburg1, Kay-Uwe Wagner6, Peter P Sayeski7, Dominik Wolf8, Wim Laleman3, Tilman Sauerbruch1, Jonel Trebicka1. 1. Department of Internal Medicine I, University of Bonn, Bonn, Germany. 2. Institute for Cell Biology, University of Bonn, Bonn, Germany. 3. Department of Liver and Biliopancreatic Disorders, University of Leuven, Leuven, Belgium. 4. Institute of Pathology, University of Bonn, Bonn, Germany. 5. Department of General and Visceral Surgery, University of Bonn, Bonn, Germany. 6. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA. 7. Department of Physiology and Functional Genomics, University of Florida, College of Medicine, Gainesville, Florida, USA. 8. Medical Clinic III, Oncology, Hematology and Rheumatology, University of Bonn, Bonn, Germany.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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 humanliver 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 humanliver 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 humancirrhosis. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Sally Yu Shi; Cynthia T Luk; Stephanie A Schroer; Min Jeong Kim; David W Dodington; Tharini Sivasubramaniyam; Lauren Lin; Erica P Cai; Shun-Yan Lu; Kay-Uwe Wagner; Richard P Bazinet; Minna Woo Journal: J Biol Chem Date: 2017-01-18 Impact factor: 5.157
Authors: Jan Görtzen; Robert Schierwagen; Jeanette Bierwolf; Sabine Klein; Frank E Uschner; Peter F van der Ven; Dieter O Fürst; Christian P Strassburg; Wim Laleman; Jörg-Matthias Pollok; Jonel Trebicka Journal: Front Physiol Date: 2015-12-02 Impact factor: 4.566