期刊
CIRCULATION
卷 129, 期 12, 页码 1276-1285出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.113.006611
关键词
atrial fibrillation; calcium; mice; ryanodine receptor calcium release channel
资金
- American Heart Association [09POST2260300, 12BGIA12050207, 12PRE11700012, 13EIA14560061]
- National Heart, Lung, and Blood Institute [R01-HL089598, R01-HL091947]
- Muscular Dystrophy Association
- Fondation Leducq
- DZHK (German Center for Cardiovascular Research)
- Deutsche Forschungsgemeinschaft [DFG MU 1376/11-1]
- IZKF Munster [Mu1/014/11]
- Canadian Institutes of Health Research [MGP6957, MOP44365]
- Heart and Stroke Foundation of Canada
- Medical Scientist Training Program Caskey Scholarship
Background The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca2+ leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca2+ release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. Methods and Results CREM-IbC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca2+ release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca2+/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca2+ release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca2+-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. Conclusions RyR2-mediated SR Ca2+ leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca2+ release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.
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