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(Circulation Research. 2009;105:784.)
© 2009 American Heart Association, Inc.

Integrative Physiology

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

Aniella Abi-Gerges, Wito Richter, Florence Lefebvre, Philippe Mateo, Audrey Varin, Christophe Heymes, Jane-Lise Samuel, Claire Lugnier, Marco Conti, Rodolphe Fischmeister, Grégoire Vandecasteele

From the Institut National de la Santé et de la Recherche Médicale UMR-S 769 (A.A.-G., F.L., P.M., A.V., R.F., G.V.), Châtenay-Malabry, France; Université Paris-Sud 11, IFR141 (A.A.-G., F.L., P.M., A.V., R.F., G.V.), Châtenay-Malabry, France; Department of Obstetrics, Gynecology, and Reproductive Sciences (W.R., M.C.), University of California, San Francisco; Institut National de la Santé et de la Recherche Médicale UMR-S 689 (C.H., J.-L.S.), Paris, France; Université Paris 7 (C.H., J.-L.S.), France; and Centre National de la Recherche Scientifique UMR 7213 (C.L.), Illkirch, France.

Correspondence to Dr Rodolphe Fischmeister, INSERM UMR-S 769, Université Paris-Sud 11, Faculté de Pharmacie, 5, Rue J.-B. Clément, F-92296 Châtenay-Malabry Cedex, France. E-mail rodolphe.fischmeister{at}inserm.fr

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.

Key Words: 3'-5' cyclic nucleotide phosphodiesterase • cardiac hypertrophy • cAMP • β-adrenergic receptors