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The antifibrotic activity of the selective IP receptor agonist ACT-333679 is mediated through inhibition of YAP/TAZ signaling

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a life-threatening and progressive scarring disease of the lung. Loss of alveolar epithelial cells, inflammation, activation of fibroblasts, appearance of myofibroblasts and excessive deposition of extracellular matrix (ECM) are central features of IPF pathogenesis, ultimately resulting in changes in tissue architecture and lung dysfunction. The two currently approved therapies, pirfenidone (Esbriet®) and nintedanib (Ofev®), significantly slow the rate of disease progression, but they do not halt or reverse tissue remodeling. Therefore, disease modifying strategies that influence (myo)fibroblast activity and ECM deposition could lead to promising new treatments. Here we demonstrate potent and effective in vitro antifibrotic properties of the selective prostacyclin (IP) receptor agonist, ACT-333679, on TGFβ1-stimulated primary human lung fibroblasts from non-diseased and IPF donors. We demonstrate that ACT-333679 inhibited fibrotic processes through elevation of cAMP, inhibition of YAP/TAZ signaling and subsequent suppression of YAP/TAZ-induced gene transcription. Our results describe attenuation of YAP/TAZ signaling through IP receptor activation as a novel mechanism that suppresses pro-fibrotic (myo)fibroblast activity and we offer a rationale to further explore the potential of IP receptor agonists for the treatment of IPF .

ORGANISM(S): Homo sapiens

PROVIDER: GSE109585 | GEO | 2019/01/24

REPOSITORIES: GEO

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Gene expression signatures for Normal-looking, fibrotic foci and hyperplastic (adjacent to fibrotic foci) area in IPF lungs

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