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Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease.

ABSTRACT: An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of cyclic adenosine 3',5'- monophosphate (cAMP) and cyclic guanosine 3',5'- monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotides can be achieved by stimulating their synthesis and/or by suppressing members of the family of cyclic nucleotide phosphodiesterases (PDEs). The heart expresses seven of the eleven major PDE subtypes - PDE1, 2, 3, 4, 5, 8, and 9. Their differential control over cAMP and cGMP signaling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. This review examines the roles of these PDEs in the failing and hypertrophied heart and summarizes experimental and clinical data that have explored the utility of targeted PDE inhibition.

SUBMITTER: Kim GE

PROVIDER: S-EPMC5665023 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease.

Kim Grace E GE Kass David A DA

Handbook of experimental pharmacology 20170101

An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of cyclic adenosine 3',5'- monophosphate (cAMP) and cyclic guanosine 3',5'- monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotid ...[more]

PMID: 27787716

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Project description:In cardiac myocytes, the second messenger cAMP is synthesized within the β-adrenergic signaling pathway upon sympathetic activation. It activates Protein Kinase A (PKA) mediated phosphorylation of multiple target proteins that are functionally critical to cardiac contractility. The dynamics of cAMP are also controlled indirectly by cGMP-mediated regulation of phosphodiesterase isoenzymes (PDEs). The nature of the interactions between cGMP and the PDEs, as well as between PDE isoforms, and how these ultimately transduce the cGMP signal to regulate cAMP remains unclear. To better understand this, we have developed mechanistically detailed models of PDEs 1-4, the primary cAMP-hydrolyzing PDEs in cardiac myocytes, and integrated them into a model of the β-adrenergic signaling pathway. The PDE models are based on experimental studies performed on purified PDEs which have demonstrated that cAMP and cGMP bind competitively to the cyclic nucleotide (cN)-binding domains of PDEs 1, 2, and 3, while PDE4 regulation occurs via PKA-mediated phosphorylation. Individual PDE models reproduce experimentally measured cAMP hydrolysis rates with dose-dependent cGMP regulation. The fully integrated model replicates experimentally observed whole-cell cAMP activation-response relationships and temporal dynamics upon varying degrees of β-adrenergic stimulation in cardiac myocytes. Simulations reveal that as a result of network interactions, reduction in the level of one PDE is partially compensated for by increased activation of others. PDE2 and PDE4 exert the strongest compensatory roles among all PDEs. In addition, PDE2 competes with other PDEs to bind and hydrolyze cAMP and is a strong regulator of PDE interactions. Finally, an increasing level of cGMP gradually out-competes cAMP for the catalytic sites of PDEs 1, 2, and 3, suppresses their cAMP hydrolysis rates, and results in amplified cAMP signaling. These results provide insights into how PDEs transduce cGMP signals to regulate cAMP and how PDE interactions affect cardiac β-adrenergic response.

Dataset Information

Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease.

Publications

Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease.

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