Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFß signalling.
Ann Rheum Dis
; 74(7): 1408-16, 2015 Jul.
Article
en En
| MEDLINE
| ID: mdl-24567525
ABSTRACT
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 ß (TGFß) 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 TGFß. sGC knockout fibroblasts were isolated from sGCI(fl/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-ß1 receptor.RESULTS:
sGC stimulation inhibited TGFß-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 TGFß-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGFß target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGFß-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGFß target gene expression, confirming that non-canonical TGFß pathways mediate the antifibrotic sGC activity.CONCLUSIONS:
We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGFß 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Esclerodermia Sistémica
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Piel
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Transducción de Señal
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Factor de Crecimiento Transformador beta
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Receptores Citoplasmáticos y Nucleares
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Fibroblastos
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Guanilato Ciclasa
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Ann Rheum Dis
Año:
2015
Tipo del documento:
Article
País de afiliación:
Alemania