Molecular patterns of the NO-sGC-cGMP pathway in progressive and regressive liver fibrosis models.

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine-monophosphate (cGMP) pathway is impaired in liver fibrosis. We investigated expression patterns of NO-sGC-cGMP components via RT-qPCR in various rat models of liver fibrosis and murine models of liver fibrosis regression. Hepatic cGMP-levels were measured chromatographically. All models demonstrated portal-hypertension and liver fibrosis, which significantly regressed in murine models. The rat models showed etiology-specific differences in NO-sGC-cGMP pathway regulation. We observed strong upregulation of sGCa1 and sGCb1 subunits in a rat choline-deficient high-fat diet model (1.75-fold, p = 0.004 and 2.04-fold, p = 0.004, respectively). The sGCa2 subunit was markedly downregulated in a rat thioacetamide model (0.66-fold, p = 0.026). The rat bile-duct-ligation model was characterized by strong upregulation of inducible nitric oxide synthetase (28.10-fold, p = 0.029). The rat thioacetamide and bile-duct-ligation models displayed downregulation of sGCb2 (0.15-fold, p = 0.002, and 0.19-fold, p = 0.029, respectively). Regardless, hepatic cGMP-levels in rat models remained unchanged. Both mouse models demonstrated upregulation of NO-sGC-cGMP pathway nodes during regression, further accompanied by increased hepatic cGMP-levels in murine carbon tetrachloride (peak-fibrosis: 3.86 nM vs. 1-week regression: 6.28 nM, p = 0.006; vs. 2-week regression: 5.49 nM, p = 0.091) and thioacetamide (peak-fibrosis: 2.87 nM vs. 1-week regression: 5.22 nM, p = 0.007; vs. 2-week regression: 6.68 nM, p < 0.001) models. The NO-sGC-cGMP pathway exhibits etiology-specific and temporal regulation patterns during liver fibrogenesis and fibrosis regression. We further highlight the functional contribution of the pathway via increases in hepatic cGMP during fibrosis regression.