Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals.
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.
Abi-Gerges
Aniella
A
INSERM UMR-S 769, Université Paris-Sud 11, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry Cedex, France.
Richter
Wito
W
Lefebvre
Florence
F
Mateo
Philippe
P
Varin
Audrey
A
Heymes
Christophe
C
Samuel
Jane-Lise
JL
Lugnier
Claire
C
Conti
Marco
M
Fischmeister
Rodolphe
R
Vandecasteele
Grégoire
G
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
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