The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice
Open accessAbstract
A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.
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Cites
Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins
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Cardiac excitation–contraction coupling
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Self-citationCalmodulin kinase II inhibition protects against structural heart disease
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Self-citationAtrial L-Type Ca 2+ Currents and Human Atrial Fibrillation
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Cited by
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Self-citationHeijman, J., Voigt, N., Nattel, S., & Dobrev, D. (2014) · Circulation Research · doi:10.1161/circresaha.114.302226 · Cited by 677
Self-citationVoigt, N., Li, N., Wang, Q., Wang, W., Trafford, A. W., Abu-Taha, I., Sun, Q., Wieland, T., Ravens, U., Nattel, S., et al. (2012) · Circulation · doi:10.1161/circulationaha.111.067306 · Cited by 624
Self-citationBrundel, B. J. J. M., Ai, X., Hills, M. T., Kuipers, M. F., Lip, G. Y. H., & de Groot, N. M. S. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00347-9 · Cited by 499
CaMKII in myocardial hypertrophy and heart failure
Anderson, M. E., Brown, J. H., & Bers, D. M. (2011) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2011.01.012 · Cited by 465
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Metadata
- Authors
- Chelu, M. G., Sarma, S., Sood, S., Wang, S., van Oort, R. J., Skapura, D. G., Li, N., Santonastasi, M., Müller, F. U., Schmitz, W., Schotten, U., Anderson, M. E., Valderrábano, M., Dobrev, D., & Wehrens, X. H. T.
- Venue
- Journal of Clinical Investigation
- Published
- 2009-06-15
- Volume
- 119
- Issue
- 7
- Pages
- 1940-51
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W1967365407
- Cited by
- 425
- References
- 54
- FWCI
- 20.96
- Type
- journal article
- Language
- en
- Open access
- green
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- Chelu, M. G., Sarma, S., Sood, S., Wang, S., van Oort, R. J., Skapura, D. G., Li, N., Santonastasi, M., Müller, F. U., Schmitz, W., Schotten, U., Anderson, M. E., Valderrábano, M., Dobrev, D., & Wehrens, X. H. T. (2009). Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. Journal of Clinical Investigation. https://doi.org/10.1172/jci37059
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