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.

Keywords: Cyclic nucleotides; Heart failure; Myocardium; Phosphodiesterases; Protein kinase A; Protein kinase G.

Figure 1

Signaling pathways and their myocardial effects coupling PDE-cAMP modulation with the activation of protein kinase A, epac, and their downstream effectors. Pathways for which published data has defined a link between a given PDE and specific downstream effects have been color coded: PDE1 in blue, PDE2A in red, and PDE3A in green.

Figure 2

Signaling pathways and their myocardial effects coupling PDE-cGMP modulation with cyclic GMP activated protein kinase (cGK1) and their downstream effects. Pathways that regulate cardiac cGMP signaling. Pathways for which published data has defined a link between a given PDE and specific downstream effects have been color coded: PDE1 in blue, PDE2A in red, and PDE5A in purple, and PDE9A in yellow.