Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction
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Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction. / Vettel, Christiane; Lindner, Marta; Dewenter, Matthias; Lorenz, Kristina; Schanbacher, Constanze; Riedel, Merle; Lämmle, Simon; Meinecke, Simone; Mason, Fleur E; Sossalla, Samuel; Geerts, Andreas; Hoffmann, Michael; Wunder, Frank; Brunner, Fabian J; Wieland, Thomas; Mehel, Hind; Karam, Sarah; Lechêne, Patrick; Leroy, Jérôme; Vandecasteele, Grégoire; Wagner, Michael; Fischmeister, Rodolphe; El-Armouche, Ali.
in: CIRC RES, Jahrgang 120, Nr. 1, 06.01.2017, S. 120-132.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction
AU - Vettel, Christiane
AU - Lindner, Marta
AU - Dewenter, Matthias
AU - Lorenz, Kristina
AU - Schanbacher, Constanze
AU - Riedel, Merle
AU - Lämmle, Simon
AU - Meinecke, Simone
AU - Mason, Fleur E
AU - Sossalla, Samuel
AU - Geerts, Andreas
AU - Hoffmann, Michael
AU - Wunder, Frank
AU - Brunner, Fabian J
AU - Wieland, Thomas
AU - Mehel, Hind
AU - Karam, Sarah
AU - Lechêne, Patrick
AU - Leroy, Jérôme
AU - Vandecasteele, Grégoire
AU - Wagner, Michael
AU - Fischmeister, Rodolphe
AU - El-Armouche, Ali
N1 - © 2016 American Heart Association, Inc.
PY - 2017/1/6
Y1 - 2017/1/6
N2 - RATIONALE: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown.OBJECTIVE: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction.METHODS AND RESULTS: Pharmacological inhibition of phosphodiesterase 2 (BAY 60-7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β-adrenoceptor-mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+ leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction.CONCLUSIONS: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.
AB - RATIONALE: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown.OBJECTIVE: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction.METHODS AND RESULTS: Pharmacological inhibition of phosphodiesterase 2 (BAY 60-7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β-adrenoceptor-mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+ leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction.CONCLUSIONS: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.
KW - Animals
KW - Arrhythmias, Cardiac/chemically induced
KW - Cardiotonic Agents/metabolism
KW - Catecholamines/toxicity
KW - Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors
KW - Dogs
KW - Female
KW - Imidazoles/pharmacology
KW - Isoproterenol/toxicity
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Myocardial Contraction/drug effects
KW - Myocardial Infarction/metabolism
KW - Triazines/pharmacology
U2 - 10.1161/CIRCRESAHA.116.310069
DO - 10.1161/CIRCRESAHA.116.310069
M3 - SCORING: Journal article
C2 - 27799254
VL - 120
SP - 120
EP - 132
JO - CIRC RES
JF - CIRC RES
SN - 0009-7330
IS - 1
ER -
