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Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis.
Gut. 2017 01; 66(1):145-155.Gut

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.

Authors+Show Affiliations

Department of Internal Medicine I, University of Bonn, Bonn, Germany.Department of Internal Medicine I, University of Bonn, Bonn, Germany.Department of Internal Medicine I, University of Bonn, Bonn, Germany.Department of Internal Medicine I, University of Bonn, Bonn, Germany.Institute for Cell Biology, University of Bonn, Bonn, Germany.Department of Liver and Biliopancreatic Disorders, University of Leuven, Leuven, Belgium.Institute of Pathology, University of Bonn, Bonn, Germany.Department of Internal Medicine I, University of Bonn, Bonn, Germany.Department of General and Visceral Surgery, University of Bonn, Bonn, Germany.Department of Internal Medicine I, University of Bonn, Bonn, Germany.Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.Department of Physiology and Functional Genomics, University of Florida, College of Medicine, Gainesville, Florida, USA.Medical Clinic III, Oncology, Hematology and Rheumatology, University of Bonn, Bonn, Germany.Department of Liver and Biliopancreatic Disorders, University of Leuven, Leuven, Belgium.Department of Internal Medicine I, University of Bonn, Bonn, Germany.Department of Internal Medicine I, University of Bonn, Bonn, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26385087

Citation

Klein, Sabine, et al. "Janus-kinase-2 Relates Directly to Portal Hypertension and to Complications in Rodent and Human Cirrhosis." Gut, vol. 66, no. 1, 2017, pp. 145-155.
Klein S, Rick J, Lehmann J, et al. Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. Gut. 2017;66(1):145-155.
Klein, S., Rick, J., Lehmann, J., Schierwagen, R., Schierwagen, I. G., Verbeke, L., Hittatiya, K., Uschner, F. E., Manekeller, S., Strassburg, C. P., Wagner, K. U., Sayeski, P. P., Wolf, D., Laleman, W., Sauerbruch, T., & Trebicka, J. (2017). Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. Gut, 66(1), 145-155. https://doi.org/10.1136/gutjnl-2015-309600
Klein S, et al. Janus-kinase-2 Relates Directly to Portal Hypertension and to Complications in Rodent and Human Cirrhosis. Gut. 2017;66(1):145-155. PubMed PMID: 26385087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. AU - Klein,Sabine, AU - Rick,Johanna, AU - Lehmann,Jennifer, AU - Schierwagen,Robert, AU - Schierwagen,Irela Gretchen, AU - Verbeke,Len, AU - Hittatiya,Kanishka, AU - Uschner,Frank Erhard, AU - Manekeller,Steffen, AU - Strassburg,Christian P, AU - Wagner,Kay-Uwe, AU - Sayeski,Peter P, AU - Wolf,Dominik, AU - Laleman,Wim, AU - Sauerbruch,Tilman, AU - Trebicka,Jonel, Y1 - 2015/09/17/ PY - 2015/03/16/received PY - 2015/08/27/revised PY - 2015/08/28/accepted PY - 2015/9/20/pubmed PY - 2017/7/19/medline PY - 2015/9/20/entrez KW - FIBROSIS KW - LIVER CIRRHOSIS KW - PORTAL HYPERTENSION SP - 145 EP - 155 JF - Gut JO - Gut VL - 66 IS - 1 N2 - 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. SN - 1468-3288 UR - https://www.unboundmedicine.com/medline/citation/26385087/Janus_kinase_2_relates_directly_to_portal_hypertension_and_to_complications_in_rodent_and_human_cirrhosis_ L2 - https://gut.bmj.com/lookup/pmidlookup?view=long&pmid=26385087 DB - PRIME DP - Unbound Medicine ER -