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Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling
  1. Christian Beyer1,
  2. Christoph Zenzmaier2,3,
  3. Katrin Palumbo-Zerr1,
  4. Rossella Mancuso1,
  5. Alfiya Distler1,
  6. Clara Dees1,
  7. Pawel Zerr1,
  8. Jingang Huang1,
  9. Christiane Maier1,
  10. Milena L Pachowsky4,
  11. Andreas Friebe5,
  12. Peter Sandner6,7,
  13. Oliver Distler8,
  14. Georg Schett1,
  15. Peter Berger2,
  16. Jörg H W Distler1
  1. 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
  3. 3Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria
  4. 4Department of Trauma and Orthopaedic Surgery, University Erlangen-Nuremberg, Erlangen, Germany
  5. 5Institute for Physiology, Julius-Maximilians-University Würzburg, Würzburg, Germany
  6. 6Bayer Health Care, Global Drug Discovery—Common Mechanism Research, Wuppertal, Germany
  7. 7Hannover Medical School, Institute of Pharmacology, Hannover, Germany
  8. 8Department of Rheumatology, University Hospital Zurich, Zürich, Switzerland
  1. Correspondence to Dr Jörg Distler, Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen D-91054, Germany; Joerg.distler{at}


Objectives We have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor β (TGFβ) signalling that mediates the antifibrotic effects of the sGC.

Methods Human fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGFβ. sGC knockout fibroblasts were isolated from sGCIfl/fl mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-β1 receptor.

Results sGC stimulation inhibited TGFβ-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGFβ-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGFβ target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGFβ-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGFβ target gene expression, confirming that non-canonical TGFβ pathways mediate the antifibrotic sGC activity.

Conclusions We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGFβ signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.

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