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

Liver fibrosis was induced in C57BL/6 J mice by either carbon tetrachloride (CCl4; 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

PH and fibrosis area peaked in the TAA model at 7.71 ± 0.57 mmHg PP and 3.87 ± 0.19% CPA; and in the CCl4 model at 9.06 ± 0.89 mmHg PP and 9.43 ± 2.59% CPA, respectively; followed by spontaneous regression at R2 (TAA: PP: 6.04 ± 0.52 mmHg, CPA: 2.90 ± 0.30%; CCl4: PP: 5.88 ± 0.52 mmHg, CPA: 6.66 ± 1.45%). RIO significantly increased hepatic cGMP levels (CCl4-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.