Abstract 11397: PDE4 Controls Basal Cyclic AMP Levels and Beta-Adrenergic Signalling in Human Atrium
Genetic studies have identified SNPs in the gene encoding the type 4D cAMP-specific phosphodiesterase (PDE4D) that confer an increased risk of cardioembolic stroke. Affected individuals were shown to exhibit a lower mRNA expression level for several PDE4D isoforms in their B-lymphocytes. However, the molecular and cellular basis for the association between a reduced PDE4D expression and stroke remains unknown. Because atrial fibrillation (AF) is the most common cause of cardioembolic stroke, we hypothesized that PDE4 inhibition in human atrial muscle might provide a rationale for AF and, in extension, cardioembolic stroke. Here we provide evidence that PDE4 is expressed in human atrial myocytes. PDE4D represents only a small portion of the total PDE activity in human atrium. However, of the four PDE4 subtypes (PDE4A-D), PDE4D is the major form expressed in this tissue. Pharmacological PDE4 inhibition with Ro 20–1724 (Ro, 10 µM) causes an increase in basal L-type Ca2+ channel current, ICa,L. Live cell imaging of single human atrial myocytes infected with an adenovirus encoding a FRET-based cAMP sensor demonstrated that Ro induces only a small increase in basal intracellular [cAMP] but dramatically delays cAMP decay following a brief (15 s) stimulation with the beta-adrenergic agonist, isoprenaline (Iso, 100 nM). Treatment with Ro similarly/also delayed the return of ISO-stimulated ICa,L to basal levels. Ro also increased the beta-adrenergic contractile response of human atrial strips and the frequency of spontaneous Ca2+ release from the sarcoplasmic reticulum (Ca2+ sparks) at baseline. Total PDE activity, and PDE4 in particular, decreased with age and was lower in AF patients than in sinus rhythm controls. Our results show that PDE4 is critical in controlling cAMP levels and thereby Ca2+ influx and release in human atrial muscle, and may hence limit the susceptibility to arrhythmias during beta-AR stimulation. Thus, our study may provide a clue for the reported association between reduced PDE4D expression and an increased incidence of cardioembolic stroke. Supported by the Fondation Leducq 06CVD02 cycAMP and the European Union contract LSHM-CT-2005-018833/EUGeneHeart.
- © 2010 by American Heart Association, Inc.