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Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart

  • Ibrahim Bedioune
  • Pierre Bobin
  • Jérôme Leroy
  • Rodolphe Fischmeister
  • Grégoire Vandecasteele
Chapter
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol.)

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.

Keywords

cAMP cGMP Cyclic nucleotide phosphodiesterases Heart failure 

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

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

None.

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Ibrahim Bedioune
    • 1
  • Pierre Bobin
    • 1
  • Jérôme Leroy
    • 1
  • Rodolphe Fischmeister
    • 1
  • Grégoire Vandecasteele
    • 1
  1. 1.Faculté de PharmacieInserm, UMR-S 1180, Univ. Paris-Sud, Université Paris-SaclayChâtenay-MalabryFrance

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