Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure

Abstract

The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) maintain physiological cardiac contractility and integrity. Cyclic nucleotide-hydrolysing phosphodiesterases (PDEs) are the prime regulators of cAMP and cGMP signalling in the heart. During heart failure (HF), the expression and activity of multiple PDEs are altered, which disrupt cyclic nucleotide levels and promote cardiac dysfunction. Given that the morbidity and mortality associated with HF are extremely high, novel therapies are urgently needed. Herein, the role of PDEs in HF pathophysiology and their therapeutic potential is reviewed. Attention is given to PDEs 1-5, and other PDEs are briefly considered. After assessing the role of each PDE in cardiac physiology, the evidence from pre-clinical models and patients that altered PDE signalling contributes to the HF phenotype is examined. The potential of pharmacologically harnessing PDEs for therapeutic gain is considered.

Alterations of Cardiac Protein Kinases in Cyclic Nucleotide-Dependent Signaling Pathways in Human Ischemic Heart Failure

“…The PDEs are the key regulators of the cAMP/cGMP signaling pathways in the heart and essential for mediating crosstalk between them (42). The majority of cardiac cyclic nucleotide hydrolysis is mediated by PDE1 in humans, but its role in cardiac physiology is largely unknown.…”

“…When it binds to cGMP, cAMP metabolism becomes less active. Thereby, cGMP serves as a positive regulator of cAMP signaling through PDE3, placing it as a critical regulator of cAMP and cGMP crosstalk (42). PDE3 has also been distinctively controlled by different NPs.…”

Cyclic nucleotide signaling and pacemaker activity

“…The unique route of cyclic nucleotides degradation is via the activity of phosphodiesterases (PDEs), positioning them as molecules of choice to manipulate and correct HR. Their pathophysiological roles have been extensively dissected in the ventricles and atria of frogs, rodents, rabbits, pigs, dogs, and humans (Mika et al, 2012, Conti et al, 2014, Dunkerly-Eyring and Kass, 2020, Preedy, 2020, Chen and Yan, 2021. However, much less is known on their contribution to cAMP and cGMP signaling cascades in the SAN cell.…”

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

“…Despite the limited expression of PDE2 in cardiomyocytes and its modest contribution to the total cAMP hydrolytic activity (~3%) under physiological conditions, PDE2 remains a well-recognized and important modulator of cardiac function [ 131 , 133 , 154 ]. PDE2 has been shown to finely coordinate critical cAMP pools governing β-AR signalling, cardiomyocyte contractility, Ca 2+ homeostasis and mitochondrial function ( Figure 2 ) [ 122 , 154 , 155 ].…”