Objectives Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC–cyclic guanosine monophosphate (cGMP) in SSc.
Methods Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823.
Results PKG1 and 2 are upregulated in SSc in a transforming growth factor-β1 (TGFβ1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC–cGMP–PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice.
Conclusions Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFβ signalling. TGFβ1 promotes its profibrotic effects through inhibition of sGC–cGMP–PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFβ1-induced ERK phosphorylation.
- systemic sclerosis
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Handling editor Josef S Smolen
Contributors AEM, CB and JHWD: designed the study. AEM, CB, A-HG, AS, C-WC, CD, CB, AR, OA, GS and JHWD: performed research and analyzed or interpreted results. AEM and JHWD: wrote the manuscript. AF and FH: provided essential tools.
Funding Grants DI 1537/8-1, DI 1537/9-1, DI 1537/11-1, DI 1537/12-1, DI 1537/13-1, DI 1537/14-1, RA 2506/3-1, AK 144/2-1, DE 2414/2-1 and DFG-CRC1181 (C01) of the Deutsche Forschungsgemeinschaft, grants J40 and A64 of the IZKF in Erlangen, grant 2013.056.1 of the Wilhelm-Sander-Foundation, grants 2014_A47, 2014_A184, 2014_A248, of the Else- Kröner-Fresenius-Foundation, grant 14-12-17-1 Bergmann of the ELAN-fonds Erlangen.
Competing interests OD has consulted for, or has received research funding from, 4D Science, Actelion, Active Biotech, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation; JHWD has consultancy relationships and/or has received research funding from Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma, Galapagos, Inventiva and Active Biotech in the area of potential treatments of SSc and is stock owner of 4D Science.
Ethics approval Ethical Review Board of the University Erlangen-Nuremberg.
Provenance and peer review Not commissioned; externally peer reviewed.
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