Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease

Handb Exp Pharmacol. 2017:243:249-269. doi: 10.1007/164_2016_82.

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.

Publication types

  • Review

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
  • Animals
  • Cardiomyopathy, Dilated / drug therapy
  • Cardiomyopathy, Dilated / metabolism*
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / antagonists & inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / antagonists & inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
  • Heart Diseases / drug therapy
  • Heart Diseases / metabolism
  • Heart Failure / drug therapy
  • Heart Failure / metabolism*
  • Humans
  • Phosphodiesterase 3 Inhibitors / therapeutic use
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • Phosphodiesterase Inhibitors / therapeutic use
  • Signal Transduction

Substances

  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase 5 Inhibitors
  • Phosphodiesterase Inhibitors
  • Cyclic AMP
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • PDE2A protein, human
  • PDE9A protein, human
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cyclic GMP