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

Year: 2009
Type: article
Abstract: 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.
DOI: 10.1172/jci37059
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
Institutions: Baylor College of Medicine, The University of Texas Health Science Center at Houston, Houston Methodist, Cornell University, University of Iowa, University of Münster, Maastricht University, Technische Universität Dresden
Language: English
Field: Medicine
Open Access status: green
Funders: March of Dimes Foundation, American Heart Association, Heart Rhythm Society, Deutsche Forschungsgemeinschaft, Fondation Leducq, Bundesministerium für Bildung und Forschung, Technische Universität Dresden, National Institutes of Health, National Heart, Lung, and Blood Institute
Awards: CaMKII in Sinus Node Physiology and Disease, Ryanodine receptor regulation in post-operative atrial fibrillation, Training Grant in Molecular Cardiology, Determining the Role of Junctophilin-2 in Cardiac Disease, European-North American Atrial Fibrillation Research Alliance (ENAFRA), Methionine sulfoxide reductase A and oxidized CaMKII in structural heart disease, Alliance for Calmodulin Kinase II Signaling in Heart Failure and Arrhythmias, Nanosecond megavolt pulse technology for cardiac stimulation and defibrillation, Mitochondrial Calmodulin Kinase II in Physiology and Disease, Regulation of Sarcoplasmic Reticulum Calcium Release in Heart Failure, Calmodulin Kinase II and Early Afterdepolarizations
OpenAlex ID: W1967365407
FWCI: 22.43
Cites: 59
Cited by: 438
Related to: 9