PT  - JOURNAL ARTICLE
AU  - Beyer, Christian
AU  - Zenzmaier, Christoph
AU  - Palumbo-Zerr, Katrin
AU  - Mancuso, Rossella
AU  - Distler, Alfiya
AU  - Dees, Clara
AU  - Zerr, Pawel
AU  - Huang, Jingang
AU  - Maier, Christiane
AU  - Pachowsky, Milena L
AU  - Friebe, Andreas
AU  - Sandner, Peter
AU  - Distler, Oliver
AU  - Schett, Georg
AU  - Berger, Peter
AU  - Distler, Jörg H W
TI  - Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling
AID  - 10.1136/annrheumdis-2013-204508
DP  - 2015 Jul 01
TA  - Annals of the Rheumatic Diseases
PG  - 1408--1416
VI  - 74
IP  - 7
4099  - http://ard.bmj.com/content/74/7/1408.short
4100  - http://ard.bmj.com/content/74/7/1408.full
SO  - Ann Rheum Dis2015 Jul 01; 74
AB  - 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.