Phosphodiesterase 2: anti-adrenergic friend or hypertrophic foe in heart disease?

Wagner, Michael; Mehel, Hind; Fischmeister, Rodolphe; El‐Armouche, Ali

doi:10.1007/s00210-016-1289-4

Cited by 14 publications

(8 citation statements)

References 9 publications

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“…50 Although this contradicts our earlier finding that adenoviral overexpression of phosphodiesterase 2 antagonizes β-AR-induced cellular hypertrophy, 29,51 we observed a small but not significant increase in cardiac size in phosphodiesterase 2-TG mice as compared with WT ( Figures 2G and 3C). Therefore, we cannot completely rule out a minor increase in heart size because of phosphodiesterase 2 overexpression.…”

Section: Phosphodiesterase 2 In Cardiac Remodelingcontrasting

confidence: 94%

Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

Vettel

Lindner

Dewenter

et al. 2017

Circulation Research

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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-adrenoceptormediated 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, Ca 2+ -spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca 2+ leakage and lower basal phosphorylation levels of Ca 2+ -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. (Circ Res. 2017;120:120-132. DOI: 10.1161/ CIRCRESAHA.116.310069.) Key Words: cardiac arrhythmia ■ catecholamine ■ cyclic GMP-stimulated phosphodiesterase ■ heart rate ■ myocardial contractionOriginal received October 2, 2016; revision received October 27, 2016; accepted October 31, 2016. In September 2016, the average time from submission to first decision for all original research papers submitted to Circulation Research was 12.73 days.From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften -ISAS -e.V., Dortmund, Germany (K.L., ...

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Section: Phosphodiesterase 2 In Cardiac Remodelingcontrasting

confidence: 94%

Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

Vettel

Lindner

Dewenter

et al. 2017

Circulation Research

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“…It has recently been shown that the activity and expression of PDE2 are increased in HF in humans and rats, and would have a cardio-protective effect by decreasing the adrenergic response [121], while inhibition of PDE2 would be anti-hypertrophic [122]. This apparent contradiction has been noted and may result from different techniques for overexpression of PDE2, leading the authors to suggest the use of PDE2 activator to resolve this contradiction [123].…”

Section: Pathophysiology Of Cardiac Natriuretic Peptidesmentioning

confidence: 99%

The Endocrine Function of the Heart: Physiology and Involvements of Natriuretic Peptides and Cyclic Nucleotide Phosphodiesterases in Heart Failure

Lugnier

Meyer

Charloux

et al. 2019

JCM

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Besides pumping, the heart participates in hydro-sodium homeostasis and systemic blood pressure regulation through its endocrine function mainly represented by the large family of natriuretic peptides (NPs), including essentially atrial natriuretic (ANP) and brain natriuretic peptides (BNP). Under normal conditions, these peptides are synthesized in response to atrial cardiomyocyte stretch, increase natriuresis, diuresis, and vascular permeability through binding of the second intracellular messenger’s guanosine 3′,5′-cyclic monophosphate (cGMP) to specific receptors. During heart failure (HF), the beneficial effects of the enhanced cardiac hormones secretion are reduced, in connection with renal resistance to NP. In addition, there is a BNP paradox characterized by a physiological inefficiency of the BNP forms assayed by current methods. In this context, it appears interesting to improve the efficiency of the cardiac natriuretic system by inhibiting cyclic nucleotide phosphodiesterases, responsible for the degradation of cGMP. Recent data support such a therapeutic approach which can improve the quality of life and the prognosis of patients with HF.

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“…Nevertheless, the conflicting findings reviewed here, indicate that the role of PDE2 in hypertrophic remodeling should be conclusively verified and careful experimental designs should be constructed. Of course, disparate experimental methods and conditions may underlie the observed incoherent results [ 180 ], yet PDE2 is evidently a valuable therapeutic target to preclude cardiac remodeling events.…”

Section: Role Of Pde2 In Cardiovascular Diseasementioning

confidence: 99%

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

Sadek

Cachorro

El‐Armouche

et al. 2020

IJMS

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Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3′,5′-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.

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Phosphodiesterase 2: anti-adrenergic friend or hypertrophic foe in heart disease?

Cited by 14 publications

References 9 publications

Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

The Endocrine Function of the Heart: Physiology and Involvements of Natriuretic Peptides and Cyclic Nucleotide Phosphodiesterases in Heart Failure

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

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