title: Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias.
abstract: Phosphodiesterases (PDEs) regulate the local concentration of 3',5' cyclic adenosine monophosphate (cAMP) within cells. cAMP activates the cAMP-dependent protein kinase (PKA). In patients, PDE inhibitors have been linked to heart failure and cardiac arrhythmias, although the mechanisms are not understood. We show that PDE4D gene inactivation in mice results in a progressive cardiomyopathy, accelerated heart failure after myocardial infarction, and cardiac arrhythmias. The phosphodiesterase 4D3 (PDE4D3) was found in the cardiac ryanodine receptor (RyR2)/calcium-release-channel complex (required for excitation-contraction [EC] coupling in heart muscle). PDE4D3 levels in the RyR2 complex were reduced in failing human hearts, contributing to PKA-hyperphosphorylated, "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias. Cardiac arrhythmias and dysfunction associated with PDE4 inhibition or deficiency were suppressed in mice harboring RyR2 that cannot be PKA phosphorylated. These data suggest that reduced PDE4D activity causes defective RyR2-channel function associated with heart failure and arrhythmias.
authors.affiliation: Clyde and Helen Wu Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Sunita
authors.initials: S
authors.lastname: Warrier
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.forename: Robert D
authors.initials: RD
authors.lastname: Harvey
authors.forename: Wito
authors.initials: W
authors.lastname: Richter
authors.forename: S-L Catherine
authors.initials: SL
authors.lastname: Jin
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000009:adverse effects; D006333:Heart Failure / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human