Beyer C, Zenzmaier C, Palumbo-Zerr K, Mancuso R, Distler A, Dees C, Zerr P, Huang J, Maier C, Pachowsky M, Friebe A, Sandner P, Distler O, Schett G, Berger P, Distler J (2015)
Publication Type: Journal article
Publication year: 2015
Book Volume: 74
Pages Range: 1408-16
Journal Issue: 7
DOI: 10.1136/annrheumdis-2013-204508
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 ? (TGF?) signalling that mediates the antifibrotic effects of the sGC.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 TGF?. sGC knockout fibroblasts were isolated from sGCI(fl/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-?1 receptor.sGC stimulation inhibited TGF?-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 TGF?-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGF? target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGF?-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGF? target gene expression, confirming that non-canonical TGF? pathways mediate the antifibrotic sGC activity.We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGF? 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.
APA:
Beyer, C., Zenzmaier, C., Palumbo-Zerr, K., Mancuso, R., Distler, A., Dees, C.,... Distler, J. (2015). Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGF? signalling. Annals of the Rheumatic Diseases, 74(7), 1408-16. https://doi.org/10.1136/annrheumdis-2013-204508
MLA:
Beyer, Christian, et al. "Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGF? signalling." Annals of the Rheumatic Diseases 74.7 (2015): 1408-16.
BibTeX: Download