Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A(2A) receptors
Por:
Llach, A, Molina, CE, Prat-Vidal, C, Fernandes, J, Casado, V, Ciruela, F, Lluis, C, Franco, R, Cinca, J, Hove-Madsen, L
Publicada:
1 mar 2011
Resumen:
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.
Filiaciones:
Llach, A:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, Cell Physiol Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp St Pau, Inst Biomed Res, Dept Cardiol, E-08193 Barcelona, Spain
Molina, CE:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, Cell Physiol Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp St Pau, Inst Biomed Res, Dept Cardiol, E-08193 Barcelona, Spain
Prat-Vidal, C:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, Cell Physiol Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp St Pau, Inst Biomed Res, Dept Cardiol, E-08193 Barcelona, Spain
Fernandes, J:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, Cell Physiol Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp St Pau, Inst Biomed Res, Dept Cardiol, E-08193 Barcelona, Spain
Casado, V:
Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Dept Biochem, Barcelona, Spain
Ciruela, F:
Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Dept Biochem, Barcelona, Spain
Lluis, C:
Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Dept Biochem, Barcelona, Spain
Franco, R:
Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Dept Biochem, Barcelona, Spain
Cinca, J:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, Cell Physiol Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp St Pau, Inst Biomed Res, Dept Cardiol, E-08193 Barcelona, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, Cell Physiol Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp St Pau, Inst Biomed Res, Dept Cardiol, E-08193 Barcelona, Spain
|