An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases

ABSTRACT

Introduction

Cyclic nucleotides, cAMP, and cGMP, are important second messengers of intracellular signaling and play crucial roles in cardiovascular biology and diseases. Cyclic nucleotide phosphodiesterases (PDEs) control the duration, magnitude, and compartmentalization of cyclic nucleotide signaling by catalyzing the hydrolysis of cyclic nucleotides. Individual PDEs modulate distinct signaling pathways and biological functions in the cell, making it a potential therapeutic target for the treatment of different cardiovascular disorders. The clinical success of several PDE inhibitors has ignited continued interest in PDE inhibitors and in PDE-target therapeutic strategies.

Areas covered

This review concentrates on recent research advances of different PDE isoforms with regard to their expression patterns and biological functions in the heart. The limitations of current research and future directions are then discussed. The current and future development of PDE inhibitors is also covered.

Expert opinion

Despite the therapeutic success of several marketed PDE inhibitors, the use of PDE inhibitors can be limited by their side effects, lack of efficacy, and lack of isoform selectivity. Advances in our understanding of the mechanisms by which cellular functions are changed through PDEs may enable the development of new approaches to achieve effective and specific PDE inhibition for various cardiac therapies.

KEYWORDS:

• Cyclic nucleotide
• phosphodiesterase (PDE)
• cardiac diseases
• PDE inhibitor

Article highlights

• PDEs play an important role in regulating the amplitude, duration, and compartmentalization of cyclic nucleotide signaling.

• Dysregulation of PDE expression and activation have been implicated in a number of cardiac diseases.

• Increasing pre-clinical and clinical evidence support that inhibiting PDEs may be attractive therapeutic strategies to treat cardiac diseases.

• It would be of value to determine the effect of targeting multiple PDEs or targeting specialized signalosomes on combating cardiac disorders in the future.

• Understanding the cellular and molecular mechanisms of PDEs enable the development of new approaches to achieve effective and specific PDE inhibition for various cardiac therapies.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Sarah Greenly for her critical reading the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was financially supported by National Institute of Health HL134910 and HL088400 (to C.Y.) and American Heart Association 17PRE33660835 (to S.C.).