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A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism.

Jones, C; Bisserier, M; Bueno-Beti, C; Bonnet, G; Neves-Zaph, S; Lee, S-Y; Milara, J; Dorfmüller, P; Humbert, M; Leopold, JA; et al. Jones, C; Bisserier, M; Bueno-Beti, C; Bonnet, G; Neves-Zaph, S; Lee, S-Y; Milara, J; Dorfmüller, P; Humbert, M; Leopold, JA; Hadri, L; Hajjar, RJ; Sassi, Y (2019) A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism. Cardiovasc Res. ISSN 1755-3245 https://doi.org/10.1093/cvr/cvz244
SGUL Authors: Bueno Beti, Carlos

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Abstract

AIMS: Cyclic adenosine monophosphate (cAMP) is the predominant intracellular second messenger that transduces signals from Gs-coupled receptors. Intriguingly, there is evidence from various cell types that an extracellular cAMP pathway is active in the extracellular space. Herein, we investigated the role of extracellular cAMP in the lung and examined whether it may act on pulmonary vascular cell proliferation and pulmonary vasculature remodeling in the pathogenesis of pulmonary hypertension (PH). METHODS AND RESULTS: The expression of cyclic AMP-metabolizing enzymes was increased in lungs from patients with PH as well as in rats treated with monocrotaline and mice exposed to Sugen/hypoxia. We report that inhibition of the endogenous extracellular cAMP pathway exacerbated Sugen/hypoxia-induced lung remodeling. We found that application of extracellular cAMP induced an increase in intracellular cAMP levels and inhibited proliferation and migration of pulmonary vascular cells in vitro. Extracellular cAMP infusion in two in vivo pulmonary hypertension models prevented and reversed pulmonary and cardiac remodeling associated with PH. Using protein expression analysis along with luciferase assays, we found that extracellular cAMP acts via the A2R/PKA/CREB/p53/Cyclin D1 pathway. CONCLUSIONS: Taken together, our data reveal the presence of an extracellular cAMP pathway in pulmonary arteries that attempts to protect the lung during PH, and suggest targeting of the extracellular cAMP signaling pathway to limit pulmonary vascular remodeling and PH. TRANSLATIONAL PERSPECTIVE: Lungs samples from patients with clinical PAH and from animals with PH display increased cyclic AMP-metabolizing enzymes expression levels. Our results indicate that an endogenous extracellular cAMP pathway is activated during PH and attempts to counteract vascular remodeling. Additionally, our study demonstrates that extracellular-cAMP inhibits chronic hypoxia-induced PH in mice and MCT-induced PH in rats by activating the A2R/PKA/CREB/p53/Cyclin D1 pathway. Importantly, PAH patients display an inactive PKA/CREB/p53/Cyclin D1 pathway that could be stimulated by extracellular-cAMP. Targeting the extracellular cAMP pathway may represent a novel therapeutic approach for the treatment of pulmonary arterial hypertension.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research following peer review. The version of record Carly Jones, Malik Bisserier, Carlos Bueno-Beti, Guillaume Bonnet, Susana Neves-Zaph, Sang-Yong Lee, Javier Milara, Peter Dorfmüller, Marc Humbert, Jane A Leopold, Lahouaria Hadri, Roger J Hajjar, Yassine Sassi, A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism, Cardiovascular Research, , cvz244 is available online at: https://doi.org/10.1093/cvr/cvz244
Keywords: Pulmonary hypertension, cyclic nucleotides, extracellular cAMP, vascular signaling, 1102 Cardiovascular Medicine And Haematology, Cardiovascular System & Hematology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Cardiovasc Res
ISSN: 1755-3245
Language: eng
Dates:
DateEvent
14 September 2019Published Online
6 September 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
AHA-17SDG33370112American Heart Associationhttp://dx.doi.org/10.13039/100000968
AHA-18IPA34170258American Heart Associationhttp://dx.doi.org/10.13039/100000968
K01 HL135474National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01HL133554National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
PubMed ID: 31529026
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/111209
Publisher's version: https://doi.org/10.1093/cvr/cvz244

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