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Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) modulate the neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple PDE isozymes with different enzymatic properties and subcellular localization regulate local pools of cyclic nucleotides and specific functions. This organization is heavily perturbed during cardiac hypertrophy and heart failure (HF), which can contribute to disease progression. Clinically, PDE inhibition has been considered a promising approach to compensate for the catecholamine desensitization that accompanies HF. Although PDE3 inhibitors, such as milrinone or enoximone, have been used clinically to improve systolic function and alleviate the symptoms of acute HF, their chronic use has proved to be detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as new potential targets to treat HF, each having a unique role in local cyclic nucleotide signalling pathways. In this Review, we describe cAMP and cGMP signalling in cardiomyocytes and present the various PDE families expressed in the heart as well as their modifications in pathological cardiac hypertrophy and HF. We also appraise the evidence from preclinical models as well as clinical data pointing to the use of inhibitors or activators of specific PDEs that could have therapeutic potential in HF.

Key points

  • Cyclic nucleotide phosphodiesterases (PDEs) hydrolyse cAMP and cGMP to modulate the neurohormonal regulation of cardiac function.

  • Multiple PDE isozymes with various enzymatic properties and subcellular localizations finely tune local pools of cyclic nucleotides and control specific cardiac functions.

  • Changes in PDE expression, activity and subcellular localization during cardiac hypertrophy and heart failure can contribute to disease progression.

  • Despite limited success in the clinical arena, evidence in the literature continues to point to inhibitors or activators of specific PDEs as promising therapies for heart failure.

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Fig. 1: Subcellular localization and activities of PDE isoforms in macromolecular complexes in cardiomyocytes.
Fig. 2: Enzymes involved in cAMP and cGMP synthesis and degradation in cardiomyocytes.

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Acknowledgements

UMR-S1180 is a member of the Laboratory of Excellence LERMIT supported by the French National Research Agency (ANR-10-LABX-33) under the programme “Investissements d’Avenir” ANR-11-IDEX-0003-01. The authors are also funded by grants from the Leducq Foundation for Cardiovascular Research (19CVD02), ERA-CVD “PDE4HEART” and ANR-16-ECVD-0007-01 to R.F. and ANR-19-CE14-0038-02 to G.V. R.K. was supported by postdoctoral fellowships from ERA-CVD and Fondation Lefoulon-Delalande.

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Kamel, R., Leroy, J., Vandecasteele, G. et al. Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure. Nat Rev Cardiol (2022). https://doi.org/10.1038/s41569-022-00756-z

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