Phosphodiesterase 4D and heart failure: a cautionary tale.
Stimulation of several G-protein-coupled receptors (GPCRs) promotes intracellular production of cyclic adenosine 3',5'-monophosphate (cAMP) and subsequently activates protein kinase A (PKA). In the heart, beta-adrenergic receptor (beta-AR) stimulation increases contractile performance and heart rate as part of the 'fight-or-flight' stress response. Molecular organisation of PKA-effector association occurs by A kinase anchoring proteins (AKAPs), which target kinase action to specific intracellular sites. Some AKAPs interact directly with specific cAMP-hydrolysing phosphodiesterase (PDE) isoforms allowing for the assembly of multi-protein complexes that create focal points of intracellular cAMP signalling. Certain PDE isoforms co-localise with PKA as part of negative feedback mechanisms which may protect from excess beta-AR stimulation of Ca2+ transporters during cardiac excitation-contraction coupling. Pharmacological PDE inhibition increases intracellular cAMP concentrations and augments excitation-contraction coupling in heart failure. However, chronic PDE inhibitor treatment causes severe cardiac side effects and increases mortality. Moreover, cAMP hydrolysing PDE activity was found decreased in heart failure which may contribute to disease progression via chronic PKA-dependent dysregulation of Ca2+ transport proteins. The authors review the contribution of PDE activity in the heart to contractile stress adaptation, the significance of altered cAMP signalling in heart failure, and the effects of PDE inhibition in heart disease.
Lehnart
Stephan E
SE
Columbia University, Clyde and Helen Wu Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, New York, NY 10032, USA.
Marks
Andrew R
AR
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006331:Heart Diseases / Q000188:drug therapy / Q000201:enzymology; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage
D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4