Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A(2A) receptors

作者：Llach Anna; Molina Cristina E; Prat Vidal Cristina; Fernandes Jacqueline; Casado Vicent; Ciruela Francisco; Lluis Carme; Franco Rafael; Cinca Juan; Hove Madsen Leif^*

来源：European Heart Journal, 2011, 32(6): 721-729.

DOI：10.1093/eurheartj/ehq464

• Adenosine
• Arrhythmia
• Atrial myocyte
• Ca2+ handling
• Ryanodine receptor

Aims Atrial fibrillation (AF) is associated with abnormal sarcoplasmic reticulum (SR) calcium release, which is promoted by adenosine A(2A) receptor (A(2A)R) activation. Here, we tested the hypothesis that abnormal calcium release in AF is linked to A(2A)R remodelling.
Methods and results Western blotting and quantitative real-time PCR were used to determine A(2A)R mRNA and protein levels in right atrial samples from patients with and without AF. Effects of A(2A)R activation on calcium handling were assessed with patch-clamp technique and confocal calcium imaging. A(2A)R mRNA levels and functional A(2A)Rs were moderately up-regulated in patients with atrial dilation and markedly up-regulated in those with AF. Accordingly, A(2A)R 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(2A)R 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(2A)Rs 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).
Conclusions Atrial fibrillation patients show increased A(2A)R 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(2A)R antagonists to reduce this abnormal calcium release points to the A(2A)R as a novel molecular target in AF.

• 出版日期2011-3