Decreased Expression and Activity of cAMP Phosphodiesterases in Cardiac Hypertrophy and Its Impact on β-Adrenergic cAMP Signals

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dc.contributor.author Abi-Gerges, Aniella
dc.contributor.author Richter, Wito
dc.contributor.author Lefebvre, Florence
dc.contributor.author Mateo, Philippe
dc.contributor.author Varin, Audrey
dc.contributor.author Heymes, Chrisrophe
dc.contributor.author Samuel, Jane-Lise
dc.contributor.author Lugnier, Claire
dc.contributor.author Conti, Marco
dc.contributor.author Fischmeister, Rodolphe
dc.contributor.author Vandecasteele, Gregoire
dc.date.accessioned 2017-10-19T12:05:45Z
dc.date.available 2017-10-19T12:05:45Z
dc.date.copyright 2009 en_US
dc.date.issued 2017-10-19
dc.identifier.issn 1524-4571 en_US
dc.identifier.uri http://hdl.handle.net/10725/6358
dc.description.abstract Rationale: Multiple cyclic nucleotide phosphodiesterases (PDEs) degrade cAMP in cardiomyocytes but the role of PDEs in controlling cAMP signaling during pathological cardiac hypertrophy is poorly defined. Objective: Evaluate the β-adrenergic regulation of cardiac contractility and characterize the changes in cardiomyocyte cAMP signals and cAMP-PDE expression and activity following cardiac hypertrophy. Methods and Results: Cardiac hypertrophy was induced in rats by thoracic aortic banding over a time period of 5 weeks and was confirmed by anatomic measurements and echocardiography. Ex vivo myocardial function was evaluated in Langendorff-perfused hearts. Engineered cyclic nucleotide-gated (CNG) channels were expressed in single cardiomyocytes to monitor subsarcolemmal cAMP using whole-cell patch-clamp recordings of the associated CNG current (ICNG). PDE variant activity and protein level were determined in purified cardiomyocytes. Aortic stenosis rats exhibited a 67% increase in heart weight compared to sham-operated animals. The inotropic response to maximal β-adrenergic stimulation was reduced by ≈54% in isolated hypertrophied hearts, along with a ≈32% decrease in subsarcolemmal cAMP levels in hypertrophied myocytes. Total cAMP hydrolytic activity as well as PDE3 and PDE4 activities were reduced in hypertrophied myocytes, because of a reduction of PDE3A, PDE4A, and PDE4B, whereas PDE4D was unchanged. Regulation of β-adrenergic cAMP signals by PDEs was blunted in hypertrophied myocytes, as demonstrated by the diminished effects of IBMX (100 μmol/L) and of both the PDE3 inhibitor cilostamide (1 μmol/L) and the PDE4 inhibitor Ro 201724 (10 μmol/L). Conclusions: β-Adrenergic desensitization is accompanied by a reduction in cAMP-PDE and an altered modulation of β-adrenergic cAMP signals in cardiac hypertrophy. en_US
dc.language.iso en en_US
dc.title Decreased Expression and Activity of cAMP Phosphodiesterases in Cardiac Hypertrophy and Its Impact on β-Adrenergic cAMP Signals en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SOM en_US
dc.author.idnumber 201402416 en_US
dc.author.department N/A en_US
dc.description.embargo N/A en_US
dc.relation.journal Circulation Research en_US
dc.journal.volume 105 en_US
dc.journal.issue 8 en_US
dc.article.pages 784-792 en_US
dc.identifier.doi https://doi.org/10.1161/CIRCRESAHA.109.197947 en_US
dc.identifier.ctation Abi-Gerges, A., Richter, W., Lefebvre, F., Mateo, P., Varin, A., Heymes, C., ... & Vandecasteele, G. (2009). Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on β-adrenergic cAMP signals. Circulation research, 105(8), 784-792. en_US
dc.author.email aniella.abigerges@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.109.197947 en_US
dc.orcid.id https://orcid.org/0000-0001-9974-4023 en_US
dc.author.affiliation Lebanese American University en_US

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