title: Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals.
abstract: BACKGROUND
  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 beta-adrenergic regulation of cardiac contractility and characterize the changes in cardiomyocyte cAMP signals and cAMP-PDE expression and activity following cardiac hypertrophy.
  
  
  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 beta-adrenergic stimulation was reduced by approximately 54% in isolated hypertrophied hearts, along with a approximately 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 beta-adrenergic cAMP signals by PDEs was blunted in hypertrophied myocytes, as demonstrated by the diminished effects of IBMX (100 micromol/L) and of both the PDE3 inhibitor cilostamide (1 micromol/L) and the PDE4 inhibitor Ro 201724 (10 micromol/L).
  
  
  CONCLUSIONS
  Beta-adrenergic desensitization is accompanied by a reduction in cAMP-PDE and an altered modulation of beta-adrenergic cAMP signals in cardiac hypertrophy.
authors.affiliation: INSERM UMR-S 769, Université Paris-Sud 11, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry Cedex, France.
authors.forename: Aniella
authors.initials: A
authors.lastname: Abi-Gerges
authors.forename: Wito
authors.initials: W
authors.lastname: Richter
authors.forename: Florence
authors.initials: F
authors.lastname: Lefebvre
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.forename: Audrey
authors.initials: A
authors.lastname: Varin
authors.forename: Christophe
authors.initials: C
authors.lastname: Heymes
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vandecasteele
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D001024:Aortic Valve Stenosis / Q000201:enzymology / Q000473:pathology; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D009929:Organ Size; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C021294:cilostamide; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015056:1-Methyl-3-isobutylxanthine