Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice
Mihail G. Chelu, … , Dobromir Dobrev, Xander H.T. Wehrens
Mihail G. Chelu, … , Dobromir Dobrev, Xander H.T. Wehrens
Published June 15, 2009
Citation Information: J Clin Invest. 2009;119(7):1940-1951. https://doi.org/10.1172/JCI37059.
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Research Article Cardiology

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

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 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.

Authors

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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Figure 2

CaMKII inhibition prevents pacing-induced increase in RyR2 phosphorylation at S2814.

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CaMKII inhibition prevents pacing-induced increase in RyR2 phosphorylati...
(A) Representative Western blots of total RyR2 and S2814-phosphorylated RyR2 at baseline and after pacing in WT and Ryr2R176Q/+ (R176Q/+) atria nontreated or treated with the CaMKII inhibitor KN-93. Bar graph showing quantification of Western blots band densities. The ratios of pS2814-RyR2 density divided by RyR2 density presented in the bar graph represent average data of 4 mice in each group. (B) Representative Western blots of total PLN and T17-phosphorylated PLN at baseline and after pacing in WT and Ryr2R176Q/+ atria nontreated or treated with the CaMKII inhibitor KN-93. Bar graph showing quantification of Western blot band densities. The ratios of pT17-PLN density divided by PLN density presented in the bar graph represent average data of 4 mice in each group. *P < 0.05, comparing indicated groups.