Impact of pharmacological sGC stimulation with Riociguat in experimental models of liver disease regression

BACKGROUND: Liver fibrosis and portal hypertension (PH) determine prognosis in chronic liver disease. In experimental models, stimulation of NO-sGC-cGMP signaling improved fibrosis, PH and inflammation. Since fibrosis and PH improve slowly after injury cessation, we investigated whether stimulating sGC activity accelerates their regression. METHODS: ; 2 µl/g, gavage 3x/week) for 12 weeks or thioacetamide (TAA; 150 mg/kg, intraperitoneal injections 3x/week) for 12 weeks, followed by 1 (R1) or 2 (R2) weeks of regression. Animals received the sGC stimulator Riociguat (RIO; 3 mg/kg, gavage 2x/day) during regression. Disease severity was assessed by portal pressure (PP), collagen proportionate area (CPA) and whole liver transcriptomics. RESULTS: -R2: 5.89 ± 0.58 nmol/L, R2 + RIO: 12.41 ± 1.98 nmol/L). While fibrosis and PH regression were not significantly different, RIO treatment attenuated the hepatic pro-inflammatory gene signatures in both models and improved metabolic pathways on a transcriptional level. CONCLUSIONS: Riociguat increases hepatic cGMP bioavailability and mitigates inflammatory and metabolic gene signatures in two experimental models of regressive liver disease. While regression of liver fibrosis and PH was not accelerated by Riociguat, our results suggest beneficial effects of sGC stimulation during regressive liver disease.