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

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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
StatePublished - Jul 1 2009

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Calcium-Calmodulin-Dependent Protein Kinases
Sarcoplasmic Reticulum
Atrial Fibrillation
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ryanodine Receptor Calcium Release Channel
Phosphorylation
Goats
Cardiac Arrhythmias

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chelu, M. G., Sarma, S., Sood, S., Wang, S., Van Oort, R. J., Skapura, D. G., ... 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.

Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. / Chelu, Mihail G.; Sarma, Satyam; Sood, Subeena; Wang, Sufen; Van Oort, Ralph J.; Skapura, Darlene G.; Li, Na; Santonastasi, Marco; Müller, Frank Ulrich; Schmitz, Wilhelm; Schotten, Ulrich; Anderson, Mark E.; Valderrábano, Miguel; Dobrev, Dobromir; Wehrens, Xander H.T.

In: Journal of Clinical Investigation, Vol. 119, No. 7, 01.07.2009, p. 1940-1951.

Research output: Contribution to journalArticle

Chelu, MG, Sarma, S, Sood, S, Wang, S, Van Oort, RJ, Skapura, DG, Li, N, Santonastasi, M, Müller, FU, Schmitz, W, Schotten, U, Anderson, ME, Valderrábano, M, Dobrev, D & Wehrens, XHT 2009, 'Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice', Journal of Clinical Investigation, vol. 119, no. 7, pp. 1940-1951.
Chelu, Mihail G. ; Sarma, Satyam ; Sood, Subeena ; Wang, Sufen ; Van Oort, Ralph J. ; Skapura, Darlene G. ; Li, Na ; Santonastasi, Marco ; Müller, Frank Ulrich ; Schmitz, Wilhelm ; Schotten, Ulrich ; Anderson, Mark E. ; Valderrábano, Miguel ; Dobrev, Dobromir ; Wehrens, Xander H.T. / Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 7. pp. 1940-1951.
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AU - Chelu, Mihail G.

AU - Sarma, Satyam

AU - Sood, Subeena

AU - Wang, Sufen

AU - Van Oort, Ralph J.

AU - Skapura, Darlene G.

AU - Li, Na

AU - Santonastasi, Marco

AU - Müller, Frank Ulrich

AU - Schmitz, Wilhelm

AU - Schotten, Ulrich

AU - Anderson, Mark E.

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AU - Dobrev, Dobromir

AU - Wehrens, Xander H.T.

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