Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

Mihail G. Chelu, Satyam Sarma, Subeena Sood, Sufen Wang, Ralph J. Van Oort, Darlene G. Skapura, Na Li, Marco Santonastasi, Frank Ulrich Müller, Wilhelm Schmitz, Ulrich Schotten, Mark E. Anderson, Miguel Valderrábano, Dobromir Dobrev, Xander H.T. Wehrens

Research output: Contribution to journalArticle

Abstract

Atrial 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 Ca 2+/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.

Original languageEnglish (US)
Pages (from-to)1940-1951
Number of pages12
JournalJournal of Clinical Investigation
Volume119
Issue number7
DOIs
StatePublished - Jul 1 2009

ASJC Scopus subject areas

  • Medicine(all)

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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, 119(7), 1940-1951. https://doi.org/10.1172/jci37059