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

Sabine Klein, Johanna Rick, Jennifer Lehmann, Robert Schierwagen, Irela Gretchen Schierwagen, Len Verbeke, Kanishka Hittatiya, Frank Erhard Uschner, Steffen Manekeller, Christian P. Strassburg, Kay Uwe Wagner, Peter P. Sayeski, Dominik Wolf, Wim Laleman, Tilman Sauerbruch, Jonel Trebicka

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Abstract

Objective Angiotensin II (AngII) activates via angiotensin-II-Type-I receptor (AT1R) Janus-kinase-2 ( JAK2)/Arhgef1 pathway and subsequently RHOA/Rhokinase (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.

Original languageEnglish (US)
Pages (from-to)145-155
Number of pages11
JournalGut
Volume66
Issue number1
DOIs
StatePublished - Sep 17 2015

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Janus Kinase 2
Portal Hypertension
Rodentia
Fibrosis
Rho Guanine Nucleotide Exchange Factors
Portal Pressure
Liver Cirrhosis
Myofibroblasts
Liver
Bile Ducts
Angiotensin II
Ligation
Hepatic Stellate Cells
End Stage Liver Disease
Carbon Tetrachloride
Varicose Veins
Peritonitis
Microspheres
Ascites
Knockout Mice

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Klein, S., Rick, J., Lehmann, J., Schierwagen, R., Schierwagen, I. G., Verbeke, L., ... Trebicka, J. (2015). 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

Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. / Klein, Sabine; Rick, Johanna; Lehmann, Jennifer; Schierwagen, Robert; Schierwagen, Irela Gretchen; Verbeke, Len; Hittatiya, Kanishka; Uschner, Frank Erhard; Manekeller, Steffen; Strassburg, Christian P.; Wagner, Kay Uwe; Sayeski, Peter P.; Wolf, Dominik; Laleman, Wim; Sauerbruch, Tilman; Trebicka, Jonel.

In: Gut, Vol. 66, No. 1, 17.09.2015, p. 145-155.

Research output: Contribution to journalArticle

Klein, S, Rick, J, Lehmann, J, Schierwagen, R, Schierwagen, IG, Verbeke, L, Hittatiya, K, Uschner, FE, Manekeller, S, Strassburg, CP, Wagner, KU, Sayeski, PP, Wolf, D, Laleman, W, Sauerbruch, T & Trebicka, J 2015, 'Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis', Gut, vol. 66, no. 1, pp. 145-155. https://doi.org/10.1136/gutjnl-2015-309600
Klein S, Rick J, Lehmann J, Schierwagen R, Schierwagen IG, Verbeke L et al. Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. Gut. 2015 Sep 17;66(1):145-155. https://doi.org/10.1136/gutjnl-2015-309600
Klein, Sabine ; Rick, Johanna ; Lehmann, Jennifer ; Schierwagen, Robert ; Schierwagen, Irela Gretchen ; Verbeke, Len ; Hittatiya, Kanishka ; Uschner, Frank Erhard ; Manekeller, Steffen ; Strassburg, Christian P. ; Wagner, Kay Uwe ; Sayeski, Peter P. ; Wolf, Dominik ; Laleman, Wim ; Sauerbruch, Tilman ; Trebicka, Jonel. / Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. In: Gut. 2015 ; Vol. 66, No. 1. pp. 145-155.
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abstract = "Objective Angiotensin II (AngII) activates via angiotensin-II-Type-I receptor (AT1R) Janus-kinase-2 ( JAK2)/Arhgef1 pathway and subsequently RHOA/Rhokinase (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.",
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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

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N2 - Objective Angiotensin II (AngII) activates via angiotensin-II-Type-I receptor (AT1R) Janus-kinase-2 ( JAK2)/Arhgef1 pathway and subsequently RHOA/Rhokinase (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.

AB - Objective Angiotensin II (AngII) activates via angiotensin-II-Type-I receptor (AT1R) Janus-kinase-2 ( JAK2)/Arhgef1 pathway and subsequently RHOA/Rhokinase (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.

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