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

作者：Thomas Sorz, Ksenia Brusilovskaya, Philipp Königshofer, Benedikt Hofer, Oleksandr Petrenko, Benedikt Simbrunner, Vlad Țâru, Katharina Bonitz, Henriette Horstmeier, Kerstin Zinober, Katharina Regnat, Carolin Lackner, Michael Trauner, Peng Sun, Ines Truebenbach, Stefan G. Kauschke, Philipp Schwabl, Thomas Reiberger · 发表于：Scientific Reports · 年份：2025 · DOI：10.1038/s41598-025-12381-0 · 被引用次数：4 · 研究领域：Liver physiology and pathology、Eicosanoids and Hypertension Pharmacology、Hormonal Regulation and Hypertension

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...