The Antifibrotic Activity of Prostacyclin Receptor Agonism Is Mediated through Inhibition of YAP/TAZ

• DOI: 10.1165/rcmb.2018-0142oc
• Publication Date: 2018-12-11T22:39:21Z
• Authors: Katarina Zmajkovi...; Katalin Menyhart; Yasmina Bauer; Rolf Studer; Berengere Renault; Marie Schnoebelen; Matthias Bolinger; Oliver Nayler; John Gatfield
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Interleukin-6; Cell Differentiation; Acetates; Fibroblasts; Receptors, Epoprostenol; Idiopathic Pulmonary Fibrosis; Extracellular Matrix; 3. Good health; 03 medical and health sciences; Gene Expression Regulation; Case-Control Studies; Pyrazines; Plasminogen Activator Inhibitor 1; Cyclic AMP; Humans; Myofibroblasts; Lung; Acyltransferases; Adaptor Proteins, Signal Transducing; Cell Proliferation; Signal Transduction

Idiopathic pulmonary fibrosis is a life-threatening progressive disease characterized by loss of alveolar epithelial cells, inflammation, and aberrant fibroblast activation. The two currently approved therapies do not halt or reverse tissue remodeling, and therefore novel disease-modifying mechanisms are needed. Our results describe YAP/TAZ inhibition through prostacyclin (IP) receptor activation as a novel mechanism that suppresses profibrotic (myo)fibroblast activity. We investigated the antifibrotic properties of the selective IP receptor agonist ACT-333679 using primary human lung fibroblasts. ACT-333679 prevented transforming growth factor β1-induced fibroblast-to-myofibroblast transition, proliferation, extracellular matrix synthesis, and IL-6 and PAI-1 secretion, and exerted relaxant effects in cell contraction assays. ACT-333679 treatment also reverted an established myofibroblast phenotype. Unbiased analysis of ACT-333679-induced whole-genome expression changes in transforming growth factor β1-treated fibroblasts identified significant attenuation of genes regulated by YAP/TAZ, two transcriptional cofactors that are essential for fibrosis. We then demonstrated that ACT-333679, via elevation of cAMP, caused YAP/TAZ nuclear exclusion and subsequent suppression of YAP/TAZ-dependent profibrotic gene transcription. In summary, we offer a rationale for further exploring the potential of IP receptor agonists for the treatment of idiopathic pulmonary fibrosis.