The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats

Philipp Schwabl, Ksenia Brusilovskaya, Paul Supper, David Bauer, Philipp Königshofer, Florian Riedl, Hubert Hayden, Claudia Daniela Fuchs, Judith Stift, Georg Oberhuber, Stefan Aschauer, DIana Bonderman, Thorsten Gnad, Alexander Pfeifer, Frank Erhard Uschner, Jonel Trebicka, Nataliya Rohr-Udilova, Bruno Karl Podesser, Markus Peck-Radosavljevic, Michael TraunerThomas Reiberger*

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Resumé

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

OriginalsprogEngelsk
Artikelnummer9372
TidsskriftScientific Reports
Vol/bind8
Antal sider13
ISSN2045-2322
DOI
StatusUdgivet - 19. jun. 2018

Fingeraftryk

Portal Pressure
Portal Hypertension
Ligation
Liver Cirrhosis
Pulmonary Hypertension
riociguat
Poisons
Vasoconstriction
Nitric Oxide
Liver

Citer dette

Schwabl, P., Brusilovskaya, K., Supper, P., Bauer, D., Königshofer, P., Riedl, F., ... Reiberger, T. (2018). The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats. Scientific Reports, 8, [9372]. https://doi.org/10.1038/s41598-018-27656-y
Schwabl, Philipp ; Brusilovskaya, Ksenia ; Supper, Paul ; Bauer, David ; Königshofer, Philipp ; Riedl, Florian ; Hayden, Hubert ; Fuchs, Claudia Daniela ; Stift, Judith ; Oberhuber, Georg ; Aschauer, Stefan ; Bonderman, DIana ; Gnad, Thorsten ; Pfeifer, Alexander ; Uschner, Frank Erhard ; Trebicka, Jonel ; Rohr-Udilova, Nataliya ; Podesser, Bruno Karl ; Peck-Radosavljevic, Markus ; Trauner, Michael ; Reiberger, Thomas. / The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats. I: Scientific Reports. 2018 ; Bind 8.
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title = "The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats",
abstract = "In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.",
author = "Philipp Schwabl and Ksenia Brusilovskaya and Paul Supper and David Bauer and Philipp K{\"o}nigshofer and Florian Riedl and Hubert Hayden and Fuchs, {Claudia Daniela} and Judith Stift and Georg Oberhuber and Stefan Aschauer and DIana Bonderman and Thorsten Gnad and Alexander Pfeifer and Uschner, {Frank Erhard} and Jonel Trebicka and Nataliya Rohr-Udilova and Podesser, {Bruno Karl} and Markus Peck-Radosavljevic and Michael Trauner and Thomas Reiberger",
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month = "6",
day = "19",
doi = "10.1038/s41598-018-27656-y",
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Schwabl, P, Brusilovskaya, K, Supper, P, Bauer, D, Königshofer, P, Riedl, F, Hayden, H, Fuchs, CD, Stift, J, Oberhuber, G, Aschauer, S, Bonderman, DI, Gnad, T, Pfeifer, A, Uschner, FE, Trebicka, J, Rohr-Udilova, N, Podesser, BK, Peck-Radosavljevic, M, Trauner, M & Reiberger, T 2018, 'The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats', Scientific Reports, bind 8, 9372. https://doi.org/10.1038/s41598-018-27656-y

The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats. / Schwabl, Philipp; Brusilovskaya, Ksenia; Supper, Paul; Bauer, David; Königshofer, Philipp; Riedl, Florian; Hayden, Hubert; Fuchs, Claudia Daniela; Stift, Judith; Oberhuber, Georg; Aschauer, Stefan; Bonderman, DIana; Gnad, Thorsten; Pfeifer, Alexander; Uschner, Frank Erhard; Trebicka, Jonel; Rohr-Udilova, Nataliya; Podesser, Bruno Karl; Peck-Radosavljevic, Markus; Trauner, Michael; Reiberger, Thomas.

I: Scientific Reports, Bind 8, 9372, 19.06.2018.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats

AU - Schwabl, Philipp

AU - Brusilovskaya, Ksenia

AU - Supper, Paul

AU - Bauer, David

AU - Königshofer, Philipp

AU - Riedl, Florian

AU - Hayden, Hubert

AU - Fuchs, Claudia Daniela

AU - Stift, Judith

AU - Oberhuber, Georg

AU - Aschauer, Stefan

AU - Bonderman, DIana

AU - Gnad, Thorsten

AU - Pfeifer, Alexander

AU - Uschner, Frank Erhard

AU - Trebicka, Jonel

AU - Rohr-Udilova, Nataliya

AU - Podesser, Bruno Karl

AU - Peck-Radosavljevic, Markus

AU - Trauner, Michael

AU - Reiberger, Thomas

PY - 2018/6/19

Y1 - 2018/6/19

N2 - In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

AB - In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

U2 - 10.1038/s41598-018-27656-y

DO - 10.1038/s41598-018-27656-y

M3 - Journal article

C2 - 29921982

AN - SCOPUS:85048745338

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 9372

ER -