Cyclic Adenosine Monophosphate Phosphodiesterase Type 4 Protects Against Atrial Arrhythmias
Por:
Molina, CE, Leroy, J, Richter, W, Xie, M, Scheitrum, C, Lee, IO, Maack, C, Rucker-Martin, C, Donzeau-Gouge, P, Verde, I, Llach, A, Hove-Madsen, L, Conti, M, Vandecasteele, G, Fischmeister, R
Publicada:
12 jun 2012
Resumen:
Objectives This study was designed to examine whether a cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE), PDE4, is expressed in human atrium and contributes to the control of electrical stability.
Background Atrial fibrillation is accompanied by a profound remodeling of membrane receptors and alterations in cAMP-dependent regulation of Ca2+ handling. Being responsible for cAMP hydrolysis, PDEs are likely to play a role in this setting. In the rodent heart, PDE4 contributes up to 60% of total cAMP-hydrolytic activity. However, its role in the human heart remains controversial.
Methods L-type Ca2+ current and spontaneous Ca2+ release were recorded in isolated human atrial myocytes. Intracellular cAMP was measured by live cell imaging using a fluorescence resonance energy transfer-based sensor. Contractile force and arrhythmias were recorded in human atrial trabeculae. PDE activity was measured in human atrial tissue from patients in sinus rhythm and permanent atrial fibrillation.
Results PDE4 is expressed in human atrial myocytes and accounts for approximately 15% of total PDE activity. PDE4D represents the major PDE4 subtype. PDE4 inhibition increased intracellular cAMP and L-type Ca2+ current and dramatically delayed their decay after a brief beta-adrenergic stimulation. PDE4 inhibition also increased the frequency of spontaneous Ca2+ release at baseline, as well as the contractile response and the incidence of arrhythmias in human atrial strips during beta-adrenergic stimulation. Total PDE activity decreased with age, and the relative PDE4 activity was lower in patients with permanent atrial fibrillation than in age-matched sinus rhythm controls.
Conclusions PDE4 is critical in controlling cAMP levels and thereby Ca2+ influx and release in human atrial muscle, hence limiting the susceptibility to arrhythmias. (J Am Coll Cardiol 2012;59:2182-90) (C) 2012 by the American College of Cardiology Foundation
Filiaciones:
Molina, CE:
DHU Torino, LabEx LERMIT, INSERM UMR S 769, Chatenay Malabry, France
Leroy, J:
DHU Torino, LabEx LERMIT, INSERM UMR S 769, Chatenay Malabry, France
Richter, W:
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Ctr Reprod Sci, San Francisco, CA 94143 USA
Xie, M:
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Ctr Reprod Sci, San Francisco, CA 94143 USA
Scheitrum, C:
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Ctr Reprod Sci, San Francisco, CA 94143 USA
Lee, IO:
Univ Saarland, Innere Med Klin 3, Homburg, Germany
Maack, C:
Univ Saarland, Innere Med Klin 3, Homburg, Germany
Rucker-Martin, C:
Hop Marie Lannelongue, DHU Torino, LabEx LERMIT, INSERM UMR S 999, F-92350 Le Plessis Robinson, France
Donzeau-Gouge, P:
Inst Hosp Jacques Cartier, Massy, France
Verde, I:
Univ Beira Interior, Ctr Invest Ciencias Saude, CICS UBI, Covilha, Portugal
Llach, A:
Hosp Santa Creu & Sant Pau, Cardiovasc Res Ctr, CSIC ICCC, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, Cardiovasc Res Ctr, CSIC ICCC, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona, Spain
Conti, M:
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Ctr Reprod Sci, San Francisco, CA 94143 USA
Vandecasteele, G:
DHU Torino, LabEx LERMIT, INSERM UMR S 769, Chatenay Malabry, France
Fischmeister, R:
Univ Paris Sud, INSERM UMR S 769, Fac Pharm, F-92296 Chatenay Malabry, France
DHU Torino, LabEx LERMIT, INSERM UMR S 769, Chatenay Malabry, France
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