Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors
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Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors. / Molina, Cristina E; Llach, Anna; Prat-Vidal, Cristina; Fernandes, Jacqueline; Casadó, Vicent; Ciruela, Francisco; Lluís, Carme; Franco, Rafael; Cinca, Juan; Hove-Madsen, Leif.
in: EUR HEART J, Jahrgang 32, Nr. 6, 03.2011, S. 721-9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors
AU - Molina, Cristina E
AU - Llach, Anna
AU - Prat-Vidal, Cristina
AU - Fernandes, Jacqueline
AU - Casadó, Vicent
AU - Ciruela, Francisco
AU - Lluís, Carme
AU - Franco, Rafael
AU - Cinca, Juan
AU - Hove-Madsen, Leif
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Adenosine A2 Receptor Antagonists
KW - Aged
KW - Atrial Fibrillation
KW - Blotting, Western
KW - Calcium
KW - Calcium Channels, L-Type
KW - Calcium Signaling
KW - Female
KW - Humans
KW - Male
KW - Middle Aged
KW - Myocytes, Cardiac
KW - RNA, Messenger
KW - Real-Time Polymerase Chain Reaction
KW - Receptor, Adenosine A2A
KW - Sarcoplasmic Reticulum
KW - Triazines
KW - Triazoles
KW - Up-Regulation
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1093/eurheartj/ehq464
DO - 10.1093/eurheartj/ehq464
M3 - SCORING: Journal article
C2 - 21177700
VL - 32
SP - 721
EP - 729
JO - EUR HEART J
JF - EUR HEART J
SN - 0195-668X
IS - 6
ER -