Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators

Matei AE, Beyer C, Gyoerfi AH, Soare A, Chen CW, Dees C, Bergmann C, Friebe A, Hofmann F, Distler O, Schett G, Distler J, Ramming A (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

DOI: 10.1136/annrheumdis-2017-212489

Abstract

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.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.PKG1 and 2 are upregulated in SSc in a transforming growth factor-?1 (TGF?1)-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.Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGF? signalling. TGF?1 promotes its profibrotic effects through inhibition of sGC-cGMP-PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGF?1-induced ERK phosphorylation.

Authors with CRIS profile

Alexandru-Emil Matei Department of Medicine 3 – Rheumatology and Immunology Christian Beyer Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose Andreas Ramming Department of Medicine 3 – Rheumatology and Immunology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH) Technische Universität München (TUM) DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE)

How to cite

APA:

Matei, A.-E., Beyer, C., Gyoerfi, A.-H., Soare, A., Chen, C.-W., Dees, C.,... Ramming, A. (2018). Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2017-212489

MLA:

Matei, Alexandru-Emil, et al. "Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators." Annals of the Rheumatic Diseases (2018).

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