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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.

journal_name

Cell

journal_title

Cell

authors

Lehnart SE,Wehrens XH,Reiken S,Warrier S,Belevych AE,Harvey RD,Richter W,Jin SL,Conti M,Marks AR

doi

10.1016/j.cell.2005.07.030

subject

Has Abstract

pub_date

2005-10-07 00:00:00

pages

25-35

issue

1

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(05)00761-0

journal_volume

123

pub_type

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