Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals
| Autor: | Rodolphe Fischmeister, Audrey Varin, Grégoire Vandecasteele, Florence Lefebvre, Jane-Lise Samuel, Claire Lugnier, Aniella Abi-Gerges, Philippe Mateo, Christophe Heymes, Wito Richter, Marco Conti |
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| Přispěvatelé: | Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty IBMX 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone Physiology Phosphodiesterase Inhibitors Phosphodiesterase 3 Adrenergic Cardiomegaly 030204 cardiovascular system & hematology Biology Quinolones Second Messenger Systems Gene Expression Regulation Enzymologic Article Contractility 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine PDE4B [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system Internal medicine 1-Methyl-3-isobutylxanthine medicine Cyclic AMP Myocyte Animals Myocytes Cardiac Rats Wistar Cells Cultured 030304 developmental biology 0303 health sciences Cilostamide Dose-Response Relationship Drug Phosphodiesterase Aortic Valve Stenosis Organ Size Myocardial Contraction Cyclic Nucleotide Phosphodiesterases Type 4 Rats Endocrinology chemistry Phosphodiesterase 4 Inhibitors Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation Research Circulation Research, American Heart Association, 2009, 105 (8), pp.784-792. ⟨10.1161/CIRCRESAHA.109.197947⟩ |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | 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 ( I CNG ). 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. |
| Databáze: | OpenAIRE |
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