[Expression and function changes of ryanodine receptors and inositol 1,4,5-triphosphate receptors of atrial myocytes during atrial fibrillation].
ABSTRACT To investigate the expression and function changes of inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) in the atrial myocytes during atrial fibrillation.
Ten adult mongrel dogs were randomly divided into 2 groups: 5 dogs underwent continuous rapid atrial pacing (500 beats/min) for twenty-four weeks to create persistent atrial fibrillation, and the other 5 size-matched dogs without pacemaker implantation were used as controls. Twenty-four weeks after the dogs' hearts were taken out and the canine atrial myocytes were isolated by enzymatic dissociation: fluorescent indicator Fluo-3/AM was added into the buffer to load the myocytes and then the Ca(2+) concentration was determined by confocal microscopy. BODIPY TR-X ryanodine was added into the buffer to stain the myocytes. Caffeine and ATP were added separately to stimulate the release of Ca(2+) from RyR.
(1) The expression of RyR in the sarcoplasmic reticulum of the atrial myocytes of the control group was (2.70 +/- 0.23), significantly higher than that of the atrial fibrillation group (0.25 +/- 0.14, P < 0.05). RyR was expressed mostly around the nucleus and only expressed in a small amount in the nucleus in the atrial fibrillation group. However, it was not expressed in the nucleus of the control group. The expression of IP3R in the atrial fibrillation group was significantly higher than that of the control group (P < 0.05). (2) After caffeine stimulation, the concentration in the atrial myocytes of the control group was (1.74 +/- 0.16), significantly higher than that of the fibrillation group (1.26 +/- 0.06, P < 0.05). (3) After ATP stimulation the Ca(2+) concentration in the atrial myocytes of the control group was (1.23 +/- 0.23), not significantly increased in comparison with that before ATP stimulation; however, the Ca(2+) concentration in the atrial myocytes of the fibrillation group after ATP stimulation was (2.29 +/- 0.65), significantly increased in comparison with that before ATP stimulation (P < 0.05).
(1) The expression of RyR is down-regulated, the function of RyR is decreased, and it is expressed in the nucleus during atrial fibrillation which shows that RyR is possibly translocated into the nucleus. (2) The expression of IP3R is up-regulated and the function of IP3R is increased during atrial fibrillation, which may be one of the major mechanisms of intracellular Ca(2+)-overload during atrial fibrillation.
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ABSTRACT: Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with increased morbidity and mortality. Current drugs for AF treatment have limited efficacy and a substantial risk of proarrhythmic side effects, making novel drug development critical. Emerging evidence suggests that abnormal intracellular calcium (Ca(2+)) signalling is a key contributor to ectopic (triggered) electrical activity in human AF. Accordingly, atrial Ca(2+)-handling abnormalities underlying ectopic activity may constitute novel mechanism-based therapeutic approaches to treat AF. This article reviews the recent evidence for a role of cellular ectopic activity in human AF pathophysiology, discusses the molecular mechanisms underlying triggered activity in human atrial myocytes, and considers their relevance to the design of novel therapeutic options.Europace 11/2012; 14 Suppl 5:v97-v105. DOI:10.1093/europace/eus282 · 3.05 Impact Factor