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Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies #MMPMID25817717
Ann Rheum Dis 2015[Aug]; 74 (8): 1621-5 PMID25817717show ga
OBJECTIVES: Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-beta signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate. METHODS: The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1-3 mg/kg twice a day for riociguat and of 3-10 mg/kg twice a day for sildenafil were used. RESULT: Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat. CONCLUSIONS: These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting.
Ann+Rheum+Dis 2015 ; 74 (8): 1621-5
