Expression and function changes of ryanodine receptors and inositol 1,4,5-triphosphate receptors of atrial myocytes during atrial fibrillation

Department of Cardiology, People's Hospital of Peking University, Beijing 100044, China.
Zhonghua yi xue za zhi 07/2004; 84(14):1196-9.
Source: PubMed


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: Many alterations in sarcoplasmic reticulum Ca(2+) handling proteins in atrial myocytes have been associated with atrial fibrillation (AF) in clinical patients, whereas the functional consequences of these alterations mostly remain unclear. To know whether or not ryanodine receptor (RyR)-mediated intracellular Ca(2+) events in AF atrial myocytes are affected by protein alterations, we investigated spontaneous Ca(2+) sparks and Ca(2+) waves in intact and permeabilized atrial myocytes of AF patients (n(patients) = 21) and normal sinus rhythm (NSR) patients (n(patients) = 22) by laser scanning confocal microscopy. It was found that the frequency, amplitude and rise time of Ca(2+) sparks were comparable between AF and NSR groups, while full width and full duration at half maximum intensity significantly increased in the AF group. Along with these changes, the frequency of small and global Ca(2+) waves increased in AF atrial myocytes. Our results clearly indicated that the spatiotemporal properties but not the frequency of Ca(2+) sparks were affected in AF atrial myocytes. In addition, the frequency of Ca(2+) waves increased. This profile of the alterations in RyR-mediated Ca(2+) events in AF atrial myocytes was different from previous studies. The underlying mechanisms, as well as possible reasons for this discrepancy, were discussed.
    No preview · Article · Apr 2008 · Cardiology
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    ABSTRACT: The roles of inositol-1,4,5-trisphosphate receptors (IP3Rs) in arrhythmia are not fully understood, especially in human beings. Recently, the reported upregulated expression of IP3Rs in atrial myocytes of atrial fibrillation (AF) subjects suggested that IP3Rs might be associated with AF. To directly understand the roles of IP3Rs in AF, we have investigated the IP3R-dependent Ca2+ events as well as the cross-talk between IP3Rs and ryanodine receptors (RyRs) in permeabilized atrial myocytes of AF and normal sinus rhythm (NSR) patients by Ca2+ imaging. In the presence of tetracaine, IP(3)R-dependent Ca2+ events in AF atrial myocytes showed increased frequency, delayed termination and broadened width, compared with NSR myocytes. Moreover, when RyRs were not inhibited, IP3 or adenophostin induced an outburst of RyR-dependent spontaneous Ca2+ sparks with the altered spatial-temporal characteristics. The activation of IP3Rs also enhanced Ca2+ waves. These effects on RyR-dependent Ca2+ signaling were significantly stronger in AF myocytes than in NSR cells and were completely blocked by 2-aminoethoxydiphenyl borate. Thus, our results suggested not only an enhanced activity of IP3Rs but also an elevated cross-talk between IP3R- and RyR-mediated Ca2+ signaling in atrial myocytes of human AF patients, a reflection of altered function of IP3Rs in AF.
    No preview · Article · Aug 2009 · Cardiology
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    ABSTRACT: During the last decades Ca(2+) has been found to play a crucial role in cardiac arrhythmias associated with heart failure and a number of congenital arrhythmia syndromes. Recent studies demonstrated that altered atrial Ca(2+) cycling may promote the initiation and maintenance of atrial fibrillation, the most common clinical arrhythmia that contributes significantly to population morbidity and mortality. This article describes physiological Ca(2+) cycling mechanisms in atrial cardiomyocytes and relates them to fundamental cellular proarrhythmic mechanisms involving Ca(2+) signaling abnormalities in the atrium during atrial fibrillation.
    No preview · Article · Jan 2012 · Advances in Experimental Medicine and Biology
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