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bioRxiv · 10.1101/2024.09.13.612935

Pharmacological Inhibition of Epac1 Protects against Pulmonary Fibrosis by Blocking FoxO3a Neddylation

Jankowski, K.·Lemay, S. E.·Lozano-Ojalvo, D.·Perez Rodriguez, L.·Sauvaget, M.·Breuils-Bonnet, S.·Formoso, K.·Jagana, V.·Zhang, S.·Milara, J.·Cortijo, J.·Turnbull, I. C.·Provencher, S.·Bonnet, S.·Orchando, J.·Lezoualch, F.·Bisserier, M.·Hadri, L.
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Abstract

BackgroundIdiopathic Pulmonary fibrosis (IPF) is characterized by progressive scarring and fibrosis within the lungs. There is currently no cure for IPF; therefore, there is an urgent need to identify novel therapeutic targets that can prevent the progression of IPF. Compelling evidence indicates that the second messenger, cyclic adenosine monophosphate (cAMP), inhibits lung fibroblast proliferation and differentiation through the classical PKA pathway. However, the contribution of the exchange protein directly activated by cAMP 1 (Epac1) to IPF pathophysiological processes is yet to be investigated. ObjectiveTo determine the role of the cAMP-binding protein Epac1 in the progression of IPF. MethodsWe used lung samples from IPF patients or healthy controls, mouse lung samples, or lung fibroblast isolated from a preclinical mouse model of PF induced by bleomycin intratracheal injection. The effect of bleomycin (BLM) treatment was determined in Epac1 knock-out mice or wild-type littermates. Epac1 expression was modulated in vitro by using lentiviral vectors or adenoviruses. The therapeutic potential of the Epac1-selective pharmacological inhibitor, AM-001, was tested in vivo and in vitro, using a bleomycin mouse model of PF and an ex vivo precision-cut lung slices (PCLs) model of human lung fibrosis. ResultsEpac1 expression was increased in the lung tissue of IPF patients, in IPF-diseased fibroblasts and in BLM-challenged mice. Furthermore, Epac1 genetic or pharmacological inhibition with AM-001 decreased normal and IPF fibroblast proliferation and the expression of profibrotic markers, SMA, TGF-{beta}/SMAD2/3, and interleukin-6 (IL-6)/STAT3 signaling pathways. Consistently, blocking Epac1 protected against BLM-induced lung injury and fibrosis, suggesting a therapeutic effect of Epac1 inhibition on PF pathogenesis and progression. Global gene expression profiling revealed a decrease in the key components of the profibrotic gene signature and neddylation pathway in Epac1-deficient lung fibroblasts and IPF human-derived PLCs. Mechanistically, the protective effect of Epac1 inhibition against PF development involves the inhibition of FoxO3a neddylation and its subsequent degradation by NEDD8, and in part, by limiting the proliferative capacity of lung-infiltrating monocytes. ConclusionsWe demonstrated that Epac1 is an important regulator of the pathological state of fibroblasts in PF and that small molecules targeting Epac1 can serve as novel therapeutic drugs against PF.

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Jankowski, K., Lemay, S. E., Lozano-Ojalvo, D., Perez Rodriguez, L., Sauvaget, M., Breuils-Bonnet, S., Formoso, K., Jagana, V., Zhang, S., Milara, J., Cortijo, J., Turnbull, I. C., Provencher, S., Bonnet, S., Orchando, J., Lezoualch, F., Bisserier, M., Hadri, L.. 2024-09-19. Pharmacological Inhibition of Epac1 Protects against Pulmonary Fibrosis by Blocking FoxO3a Neddylation. https://doi.org/10.1101/2024.09.13.612935

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