Activation of Soluble Guanylate Cyclase in Liver Fibrosis and Portal Hypertension
In liver cirrhosis intrahepatic vascular resistance is increased, leading to portal hypertension (PHT). PHT may cause serious complications such as variceal bleeding and development of ascites and is associated with significant mortality. Pathophysiological mechanisms that drive the development and progression of PHT involve vascular remodelling, hepatic stellate cell activation and fibrogenesis.
Current PHT treatment options are limited to non-selective beta blockers and the management of PHT complications. Thus, there is an unmet clinical need for novel treatment options. The modulation of nitric oxide (NO) as an important regulator of vasotonus and cellular homeostasis such as by stimulation or activation of the soluble guanlyte cyclase (sGC) represent an interesting target for treatment of portal hypertension. During my thesis work I will investige if sGC modulation of stimulators or activators have a therapeutic effect on portal pressure and liver fibrosis.
• to investigate the effects of sGC stimulation in animal models of toxic or cholestatic liver cirrhosis and portal hypertension
• to compare the efficacy of sGC stimulators versus activators versus PDE5 inhibitors in an animal model of cholestatic cirrhosis and portal hypertension.
• to decipher the cell-specific effects of sGC modulators in hepatic non-parenchymal cells, i.e. hepatic stellate cells (HSCs), Kupfer cells (KCs) and liver sinusoidal endothelial cells (LSECs).
Methods and Skills:
Molecular biological techniques (DNA/RNA isolation, PCR, Western blot); genetic modifications; cell culture; flow cytometry; protein isolation and separation; secondary metabolites isolation; UPLC analysis; chromatographic techniques; microscope techniques
Schwabl P, Brusilovskaya K, Riedl F, Bauer D, Strobel B, Fida S, Supper P, Hayden H, Trauner M, Peck-Radosavljevic M, Reiberger T: The soluble guanylyl cyclase stimulator riociguat reduces liver fibrosis and portal pressure in cirrhotic rats. Gastroenterol 53: 515, 2015; OEGGH Annual Meeting 2015 in Salzburg, Austria
Schwabl P, Brusilovskaya K, Riedl F, Bauer DJ, Strobel B, Supper P, Hayden H, Trauner M, Podesser BK, Wochner K, Peck-Radosavljevic M, Reiberger T: The guanylyl cyclase stimulator riociguat reduces liver fibrosis and portal pressure in cirrhotic rats. Hepatology 62 (Suppl.1): 954A, 2015; AASLD Annual Meeting 2015 in San Francisco, USA
Schwabl P, Brusilovskaya K, Riedl F, Bauer D, Strobel B, Supper P, Rohr-Udilova N, Hayden H, Podesser B, Reiberger T, Trauner M, Peck-Radosavljevic M: The soluble guanylyl cyclase stimulator riociguat reduces liver fibrosis and portal pressure in cirrhotic rats. J Hepatol 64 (Suppl.2): S140, 2016;. EASL Annual Meeting / International Liver Congress 2016 in Barcelona, Spain
Königshofer P, Brusilovskaya K, Schwabl P, Podesser BK, Trauner M, Reiberger T: Invasive hemodynamic characterization of the portal-hypertensive syndrome in cirrhotic rats. J Vis Exp (submitted)
Schwabl P, Brusilovskaya K, Supper P, Bauer D, Königshofer P, Riedl F, Hayden H, Fuchs C, Stift J, Oberhuber G, Aschauer S, Bonderman D, Gnad T, Pfeifer A, Uschner F, Trebicka J, Rohr-Udilova N, Podesser B, Peck-Radosavljevic M, Trauner M, Reiberger T: The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats. J Hepatol (submitted)
Brusilovskaya K, Königshofer P, Lampach D, Szodl A, Supper P, Trauner M, Reiberger T, Schwabl P: Targeting the nitric-oxide downstream pathway in bile-duct ligated rats to improve portal hypertension and liver fibrosis. Submitted abstract to EASL Annual Meeting / International Liver Congress 2018 in Paris, France