Carly Jones1, Malik Bisserier1, Carlos Bueno-Beti1, Guillaume Bonnet1, Susana Neves-Zaph2,3, Sang-Yong Lee4, Javier Milara5,6,7, Peter Dorfmüller8,9,10, Marc Humbert8,9,10, Jane A Leopold11, Lahouaria Hadri1, Roger J Hajjar12, Yassine Sassi1. 1. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. 2. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, 10029 NY; USA. 3. Systems Biology Center, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, 10029 NY; USA. 4. Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie I, Universität Bonn, Bonn, Germany. 5. Health Research Institute INCLIVA, Valencia, Spain. 6. Pharmacy Unit, University Clinic Hospital, Valencia, Spain. 7. CIBERES, Health Institute Carlos III, Valencia, Spain. 8. Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France. 9. Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre, France. 10. INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France. 11. Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 12. Phospholamban Foundation, Amsterdam, Netherlands.
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 remodelling 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 remodelling. 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 PH models prevented and reversed pulmonary and cardiac remodelling 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 signalling pathway to limit pulmonary vascular remodelling and PH. Published on behalf of the European Society of Cardiology. All rights reserved.
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 remodelling 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 remodelling. 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 PH models prevented and reversed pulmonary and cardiac remodelling 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 signalling pathway to limit pulmonary vascular remodelling and PH. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Sarah L Sayner; Chung-Sik Choi; Marcy E Maulucci; K C Ramila; Chun Zhou; April K Scruggs; Thomas Yarbrough; Leslie A Blair; Judy A King; Roland Seifert; Volkhard Kaever; Natalie N Bauer Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-02-13 Impact factor: 6.011