Journal
CIRCULATION
Volume 128, Issue 16, Pages 1748-1757Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.113.003313
Keywords
angiotensin II; arrhythmias; cardiac; atrial fibrillation; calcium-calmodulin-dependent protein kinase type II; reactive oxygen species
Funding
- National Institutes of Health (NIH) [R01-HL 079031, R01-HL096652, R01-HL070250, R01-HL071140, R01-HL0909050, RR026293]
- European Union
- University of Iowa Research Foundation
- 2 Fondation Leducq grants [08CVD01, 07CVD03]
- DZHK (German Center for Cardiovascular Research)
- Deutsche Forschungsgemeinschaft (DFG) [TPA03 SFB 1002, GRK 1816 RP3]
- Heisenberg grant [MA 1982/4-2]
- American Heart Association [10POST3620047]
- Fondation Leducq
- AHA [12BGIA12050207, 13EIA14560061]
- NIH [R01-HL089598, R01-HL091947]
- Kenneth M. Rosen Fellowship from the Heart Rhythm Society
- Max Schaldach Fellowship from the Heart Rhythm Society
- University of Iowa Cardiovascular Research Center Interdisciplinary Research Fellowship
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Background Atrial fibrillation (AF) is a growing public health problem without adequate therapies. Angiotensin II and reactive oxygen species are validated risk factors for AF in patients, but the molecular pathways connecting reactive oxygen species and AF are unknown. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) has recently emerged as a reactive oxygen species-activated proarrhythmic signal, so we hypothesized that oxidized CaMKII could contribute to AF. Methods and Results We found that oxidized CaMKII was increased in atria from AF patients compared with patients in sinus rhythm and from mice infused with angiotensin II compared with mice infused with saline. Angiotensin II-treated mice had increased susceptibility to AF compared with saline-treated wild-type mice, establishing angiotensin II as a risk factor for AF in mice. Knock-in mice lacking critical oxidation sites in CaMKII (MM-VV) and mice with myocardium-restricted transgenic overexpression of methionine sulfoxide reductase A, an enzyme that reduces oxidized CaMKII, were resistant to AF induction after angiotensin II infusion. Conclusions Our studies suggest that CaMKII is a molecular signal that couples increased reactive oxygen species with AF and that therapeutic strategies to decrease oxidized CaMKII may prevent or reduce AF.
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