Phosphodiesterase-2 is up-regulated in human failing hearts and blunts β-adrenergic responses in cardiomyocytes

TY - JOUR

T1 - Phosphodiesterase-2 is up-regulated in human failing hearts and blunts β-adrenergic responses in cardiomyocytes

AU - Mehel, Hind

AU - Emons, Julius

AU - Vettel, Christiane

AU - Wittköpper, Katrin

AU - Seppelt, Danilo

AU - Dewenter, Matthias

AU - Lutz, Susanne

AU - Sossalla, Samuel

AU - Maier, Lars S

AU - Lechêne, Patrick

AU - Leroy, Jérôme

AU - Lefebvre, Florence

AU - Varin, Audrey

AU - Eschenhagen, Thomas

AU - Nattel, Stanley

AU - Dobrev, Dobromir

AU - Zimmermann, Wolfram-Hubertus

AU - Nikolaev, Viacheslav O

AU - Vandecasteele, Grégoire

AU - Fischmeister, Rodolphe

AU - El-Armouche, Ali

N1 - Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

PY - 2013/10/22

Y1 - 2013/10/22

N2 - OBJECTIVES: This study investigated whether myocardial phosphodiesterase-2 (PDE2) is altered in heart failure (HF) and determined PDE2-mediated effects on beta-adrenergic receptor (β-AR) signaling in healthy and diseased cardiomyocytes.BACKGROUND: Diminished cyclic adenosine monophosphate (cAMP) and augmented cyclic guanosine monophosphate (cGMP) signaling is characteristic for failing hearts. Among the PDE superfamily, PDE2 has the unique property of being able to be stimulated by cGMP, thus leading to a remarkable increase in cAMP hydrolysis mediating a negative cross talk between cGMP and cAMP signaling. However, the role of PDE2 in HF is poorly understood.METHODS: Immunoblotting, radioenzymatic- and fluorescence resonance energy transfer-based assays, video edge detection, epifluorescence microscopy, and L-type Ca2(+) current measurements were performed in myocardial tissues and/or isolated cardiomyocytes from human and/or experimental HF, respectively.RESULTS: Myocardial PDE2 expression and activity were ~2-fold higher in advanced human HF. Chronic β-AR stimulation via catecholamine infusions in rats enhanced PDE2 expression ~2-fold and cAMP hydrolytic activity ~4-fold, which correlated with blunted cardiac β-AR responsiveness. In diseased cardiomyocytes, higher PDE2 activity could be further enhanced by stimulation of cGMP synthesis via nitric oxide donors, whereas specific PDE2 inhibition partially restored β-AR responsiveness. Accordingly, PDE2 overexpression in healthy cardiomyocytes reduced the rise in cAMP levels and L-type Ca2(+) current amplitude, and abolished the inotropic effect following acute β-AR stimulation, without affecting basal contractility. Importantly, PDE2-overexpressing cardiomyocytes showed marked protection from norepinephrine-induced hypertrophic responses.CONCLUSIONS: PDE2 is markedly up-regulated in failing hearts and desensitizes against acute β-AR stimulation. This may constitute an important defense mechanism during cardiac stress, for example, by antagonizing excessive β-AR drive. Thus, activating myocardial PDE2 may represent a novel intracellular antiadrenergic therapeutic strategy in HF.

AB - OBJECTIVES: This study investigated whether myocardial phosphodiesterase-2 (PDE2) is altered in heart failure (HF) and determined PDE2-mediated effects on beta-adrenergic receptor (β-AR) signaling in healthy and diseased cardiomyocytes.BACKGROUND: Diminished cyclic adenosine monophosphate (cAMP) and augmented cyclic guanosine monophosphate (cGMP) signaling is characteristic for failing hearts. Among the PDE superfamily, PDE2 has the unique property of being able to be stimulated by cGMP, thus leading to a remarkable increase in cAMP hydrolysis mediating a negative cross talk between cGMP and cAMP signaling. However, the role of PDE2 in HF is poorly understood.METHODS: Immunoblotting, radioenzymatic- and fluorescence resonance energy transfer-based assays, video edge detection, epifluorescence microscopy, and L-type Ca2(+) current measurements were performed in myocardial tissues and/or isolated cardiomyocytes from human and/or experimental HF, respectively.RESULTS: Myocardial PDE2 expression and activity were ~2-fold higher in advanced human HF. Chronic β-AR stimulation via catecholamine infusions in rats enhanced PDE2 expression ~2-fold and cAMP hydrolytic activity ~4-fold, which correlated with blunted cardiac β-AR responsiveness. In diseased cardiomyocytes, higher PDE2 activity could be further enhanced by stimulation of cGMP synthesis via nitric oxide donors, whereas specific PDE2 inhibition partially restored β-AR responsiveness. Accordingly, PDE2 overexpression in healthy cardiomyocytes reduced the rise in cAMP levels and L-type Ca2(+) current amplitude, and abolished the inotropic effect following acute β-AR stimulation, without affecting basal contractility. Importantly, PDE2-overexpressing cardiomyocytes showed marked protection from norepinephrine-induced hypertrophic responses.CONCLUSIONS: PDE2 is markedly up-regulated in failing hearts and desensitizes against acute β-AR stimulation. This may constitute an important defense mechanism during cardiac stress, for example, by antagonizing excessive β-AR drive. Thus, activating myocardial PDE2 may represent a novel intracellular antiadrenergic therapeutic strategy in HF.

KW - Adrenergic beta-Agonists

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - Catecholamines

KW - Cells, Cultured

KW - Cyclic Nucleotide Phosphodiesterases, Type 2

KW - Dogs

KW - Female

KW - Heart Failure

KW - Humans

KW - Male

KW - Mice

KW - Middle Aged

KW - Myocytes, Cardiac

KW - Rats

KW - Rats, Wistar

KW - Receptors, Adrenergic, beta

KW - Up-Regulation

KW - Young Adult

U2 - 10.1016/j.jacc.2013.05.057

DO - 10.1016/j.jacc.2013.05.057

M3 - SCORING: Journal article

C2 - 23810893

VL - 62

SP - 1596

EP - 1606

JO - J AM COLL CARDIOL

JF - J AM COLL CARDIOL

SN - 0735-1097

IS - 17

ER -