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Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart

  • Chapter
  • First Online:
Microdomains in the Cardiovascular System

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 3))

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cAMP and cGMP, thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families which are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP controlling specific cell functions in response to various neurohormonal stimuli. In myocardium, the PDE3 and PDE4 families are predominant to degrade cAMP and thereby regulate cardiac excitation-contraction coupling. PDE3 inhibitors are positive inotropes and vasodilators in human, but their use is limited to acute heart failure and intermittent claudication. PDE5 is particularly important to degrade cGMP in vascular smooth muscle, and PDE5 inhibitors are used to treat erectile dysfunction and pulmonary hypertension. However, these drugs do not seem efficient in heart failure with preserved ejection fraction. There is experimental evidence that these PDEs as well as other PDE families including PDE1, PDE2 and PDE9 may play important roles in cardiac diseases such as hypertrophy and heart failure. After a brief presentation of the cyclic nucleotide pathways in cardiac cells and the major characteristics of the PDE superfamily, this chapter will present their role in cyclic nucleotide compartmentation and the current use of PDE inhibitors in cardiac diseases together with the recent research progresses that could lead to a better exploitation of the therapeutic potential of these enzymes in the future.

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Abbreviations

AC:

Adenylyl cyclases

AKAP:

A-kinase anchoring protein

ANP:

Atrial natriuretic peptide

BNP:

Brain natriuretic peptide

CaM:

Calmodulin

CaMKII:

Ca2+/calmodulin-dependent kinase II

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

CN:

Cyclic nucleotides

CNP:

C-type natriuretic peptide

ECC:

Excitation-contraction coupling

Epac:

Exchange protein directly activated by cAMP

ERK:

Extracellular signal-regulated kinase

FRET:

Förster resonance energy transfer

GAF:

cGMP-stimulated phosphodiesterases, Anabaena adenylyl cyclases, Fhla transcription factor

GC:

Guanylyl cyclase

HF:

Heart failure

ICER:

Inducible-cAMP early repressor

I/R:

Ischemia/reperfusion

KO:

Knockout

LTCC:

L-type Ca2+ channels

mAKAP:

Muscle AKAP

NO:

Nitric oxide

NOS:

NO synthase

PDE:

Cyclic nucleotide phosphodiesterase

pGC:

Particulate guanylyl cyclase

PGE:

Prostaglandin

PI3Kγ:

Phosphoinositide 3-kinase, γ isoform

PKA:

cAMP-dependent protein kinase

PKG:

cGMP-dependent protein kinase

PLB:

Phospholamban

RyR2:

Ryanodine receptor type 2

SERCA:

Sarco-endoplasmic reticulum Ca2+-ATPase

sGC:

Soluble guanylyl cyclase

SR:

Sarcoplasmic reticulum

TnI:

Troponin I

β-ARs:

β-adrenergic receptors

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Acknowledgements

This work was supported by the Fondation de France (to GV) and the Agence Nationale de la Recherche 2010 BLAN 1139-01 (to GV). PB and IB were supported by PhD fellowships from the region Ile-de-France (CORDDIM) and Fondation pour la Recherche Médicale.

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Authors and Affiliations

  1. Faculté de Pharmacie, Inserm, UMR-S 1180, Univ. Paris-Sud, Université Paris-Saclay, F-92296, Châtenay-Malabry, France

    Ibrahim Bedioune, Pierre Bobin, Jérôme Leroy, Rodolphe Fischmeister & Grégoire Vandecasteele

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  1. Ibrahim Bedioune
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  2. Pierre Bobin
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  3. Jérôme Leroy
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  4. Rodolphe Fischmeister
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  5. Grégoire Vandecasteele
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Correspondence to Rodolphe Fischmeister or Grégoire Vandecasteele .

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Editors and Affiliations

  1. Institute of Experimental Cardiovascular Research, University Medical Center, Hamburg-Eppendorf, Germany

    Viacheslav Nikolaev

  2. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Manuela Zaccolo

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Bedioune, I., Bobin, P., Leroy, J., Fischmeister, R., Vandecasteele, G. (2017). Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart. In: Nikolaev, V., Zaccolo, M. (eds) Microdomains in the Cardiovascular System. Cardiac and Vascular Biology, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-54579-0_6

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