Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A <inf>2A</inf> receptors

Anna Llach, Cristina E. Molina, Cristina Prat-Vidal, Jacqueline Fernandes, Vicent Casad, Francisco Ciruela, Carme Llus, Rafael Franco, Juan Cinca, Leif Hove-Madsen

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Abstract

Aims Atrial fibrillation (AF) is associated with abnormal sarcoplasmic reticulum (SR) calcium release, which is promoted by adenosine A 2 receptor (A 2R) activation. Here, we tested the hypothesis that abnormal calcium release in AF is linked to A 2R remodelling.Methods and resultsWestern blotting and quantitative real-time PCR were used to determine A 2R mRNA and protein levels in right atrial samples from patients with and without AF. Effects of A 2R activation on calcium handling were assessed with patch-clamp technique and confocal calcium imaging. A 2R mRNA levels and functional A 2Rs were moderately up-regulated in patients with atrial dilation and markedly up-regulated in those with AF. Accordingly, A 2R stimulation significantly increased ryanodine receptor phosphorylation in AF patients, and spontaneous calcium waves increased moderately in myocytes from patients with atrial dilation and strongly in patients with AF (2.2 ± 2.1 to 14.3 ± 8.8 min -1, n 6, P 0.01). Moreover, the high baseline level of calcium waves in AF was reduced by A 2R antagonists (3.5 ± 2.0 to 1.3 ± 1.3 min -1, n 6, P 0.007) or adenosine deaminase (1.7 ± 1.5 to 0.5 ± 0.6 min -1, n 10, P 0.02) suggesting that A 2Rs are activated by endogenous adenosine. Indeed, intracellular perfusion with adenosine significantly increased the calcium wave frequency (1.1 ± 0.8 to 8.2 ± 3.3 min -1, n 8), whereas adenosine removal from the cytosol decreased it (2.1 ± 0.9 to 0.3 ± 0.3 min -1, n 8, P 0.04).Conclusion sAtrial fibrillation patients show increased A 2R expression that may account for the high baseline level of spontaneous SR calcium release seen in myocytes from these patients, and the ability of A 2R antagonists to reduce this abnormal calcium release points to the A 2R as a novel molecular target in AF. © 2010 The Author.
Original languageEnglish
Pages (from-to)721-729
JournalEuropean Heart Journal
Volume32
Issue number6
DOIs
Publication statusPublished - 1 Mar 2011

Keywords

  • Adenosine
  • Arrhythmia
  • Atrial myocyte
  • Ca handling 2+
  • Ryanodine receptor

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    Llach, A., Molina, C. E., Prat-Vidal, C., Fernandes, J., Casad, V., Ciruela, F., Llus, C., Franco, R., Cinca, J., & Hove-Madsen, L. (2011). Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A <inf>2A</inf> receptors. European Heart Journal, 32(6), 721-729. https://doi.org/10.1093/eurheartj/ehq464