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Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis
  1. Christian Beyer1,
  2. Nicole Reich1,
  3. Sonia C Schindler1,
  4. Alfiya Akhmetshina1,
  5. Clara Dees1,
  6. Michal Tomcik1,
  7. Claudia Hirth-Dietrich2,
  8. Georges von Degenfeld2,
  9. Peter Sandner2,
  10. Oliver Distler3,
  11. Georg Schett1,
  12. Jörg H W Distler1
  1. 1Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Common Mechanism Research, Bayer HealthCare, Wuppertal, Germany
  3. 3Center of Experimental Rheumatology, Zurich, Switzerland
  1. Correspondence to Jörg Distler, Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany; Joerg.distler{at}uk-erlangen.de

Abstract

Background Fibrosis and vascular disease are cardinal features of systemic sclerosis (SSc). Stimulators of soluble guanylate cyclase (sGC) are vasoactive drugs that are currently being evaluated in phase III clinical trials for pulmonary arterial hypertension.

Objective To study the antifibrotic potency of sGC stimulators.

Methods The effect of the sGC stimulator BAY 41-2272 on the release of collagen from dermal fibroblasts was examined. The antifibrotic effects of BAY 41-2272 on prevention and regression of fibrosis in bleomycin-induced dermal fibrosis and in Tsk-1 mice were also studied. Telemetric blood pressure studies in conscious mice were used to study potential hypotensive effects of sGC stimulation.

Results sGC stimulation with BAY 41-2272 dose-dependently inhibited collagen release in dermal fibroblasts from patients with SSc and healthy individuals. Furthermore, BAY 41-2272 stopped the development of bleomycin-induced dermal fibrosis and skin fibrosis in Tsk-1 mice, preventing dermal and hypodermal thickening, reducing the numbers of myofibroblasts and reducing the hydroxyproline content. In addition, BAY 41-2272 was highly effective in the treatment of established fibrosis in the modified models of bleomycin-induced skin fibrosis and Tsk-1 mice. Treatment with sGC stimulators was well tolerated. Relevant antifibrotic doses of BAY 41-2272 did not affect systemic blood pressure and heart rate in mice.

Conclusions These findings demonstrate potent antifibrotic effects and good tolerability of sGC stimulators in various experimental models of SSc. Given their potential vasoactive properties, sGC stimulators may be promising candidates for the dual treatment of fibrosis and vascular disease in SSc.

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Footnotes

  • Funding CB: Research scholar at the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen; grant from the Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsförderung (ELAN). MT: CMH research projects No 00000023728. JHWD: grant A40 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen; grants from the Deutsche Forschungsgesellschaft (grants DI 1537/1-1, DI 1537/2-1, DI 1537/4-1, AK 144/1-1, SCHE 1583/7-1, and DI 1537/5-1); and the Career Support Award of Medicine of the Ernst Jung Foundation.

  • Competing interests JHWD is member of the advisory board of Bayer HealthCare and has received speaker fees from Bayer HealthCare; and is also stock owner of 4D Science GmbH, which cooperates with Bayer HealthCare. CH-D, GvD, PS are employees of Bayer HealthCare.

  • Ethics approval Ethical committee of the Universit of Erlangen-Nuremberg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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