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Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors

Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A... AimsAtrial fibrillation (AF) is associated with abnormal sarcoplasmic reticulum (SR) calcium release, which is promoted by adenosine A2A receptor (A2AR) activation. Here, we tested the hypothesis that abnormal calcium release in AF is linked to A2AR remodelling.Methods and resultsWestern blotting and quantitative real-time PCR were used to determine A2AR mRNA and protein levels in right atrial samples from patients with and without AF. Effects of A2AR activation on calcium handling were assessed with patch-clamp technique and confocal calcium imaging. A2AR mRNA levels and functional A2ARs were moderately up-regulated in patients with atrial dilation and markedly up-regulated in those with AF. Accordingly, A2AR 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 A2AR 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 A2ARs 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).ConclusionsAtrial fibrillation patients show increased A2AR expression that may account for the high baseline level of spontaneous SR calcium release seen in myocytes from these patients, and the ability of A2AR antagonists to reduce this abnormal calcium release points to the A2AR as a novel molecular target in AF. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors

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References (41)

Publisher
Oxford University Press
Copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: journals.permissions@oup.com
Subject
CLINICAL RESEARCH
ISSN
0195-668X
eISSN
1522-9645
DOI
10.1093/eurheartj/ehq464
pmid
21177700
Publisher site
See Article on Publisher Site

Abstract

AimsAtrial fibrillation (AF) is associated with abnormal sarcoplasmic reticulum (SR) calcium release, which is promoted by adenosine A2A receptor (A2AR) activation. Here, we tested the hypothesis that abnormal calcium release in AF is linked to A2AR remodelling.Methods and resultsWestern blotting and quantitative real-time PCR were used to determine A2AR mRNA and protein levels in right atrial samples from patients with and without AF. Effects of A2AR activation on calcium handling were assessed with patch-clamp technique and confocal calcium imaging. A2AR mRNA levels and functional A2ARs were moderately up-regulated in patients with atrial dilation and markedly up-regulated in those with AF. Accordingly, A2AR 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 A2AR 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 A2ARs 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).ConclusionsAtrial fibrillation patients show increased A2AR expression that may account for the high baseline level of spontaneous SR calcium release seen in myocytes from these patients, and the ability of A2AR antagonists to reduce this abnormal calcium release points to the A2AR as a novel molecular target in AF.

Journal

European Heart JournalOxford University Press

Published: Mar 22, 2011

Keywords: Adenosine Arrhythmia Atrial myocyte Ca 2+ handling Ryanodine receptor

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