Oxidized Ca2+/Calmodulin-Dependent Protein Kinase II Triggers Atrial Fibrillation

Anil Purohit, Adam G. Rokita, Xiaoqun Guan, Biyi Chen, Olha M. Koval, Niels Voigt, Stefan Neef, Thomas Sowa, Zhan Gao, Elizabeth D. Luczak, Hrafnhildur Stefansdottir, Andrew C. Behunin, Na Li, Ramzi N. El-Accaoui, Baoli Yang, Paari Dominic Swaminathan, Robert M. Weiss, Xander H.T. Wehrens, Long Sheng Song, Dobromir DobrevLars S. Maier, Mark E. Anderson

Research output: Contribution to journalArticle

Abstract

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 Ca/calmodulin-dependent protein kinase II (CaMKII) has recently emerged as a reactive oxygen species-activated proarrhythmic signal, so we hypothesized that oxidized CaMKIIδ 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 CaMKIIδ (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.

Original languageEnglish (US)
Pages (from-to)1748-1757
Number of pages10
JournalCirculation
Volume128
Issue number16
DOIs
StatePublished - Oct 15 2013
Externally publishedYes

Keywords

  • angiotensin II
  • arrhythmias, cardiac
  • atrial fibrillation
  • calcium-calmodulin-dependent protein kinase type II
  • reactive oxygen species

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Purohit, A., Rokita, A. G., Guan, X., Chen, B., Koval, O. M., Voigt, N., Neef, S., Sowa, T., Gao, Z., Luczak, E. D., Stefansdottir, H., Behunin, A. C., Li, N., El-Accaoui, R. N., Yang, B., Swaminathan, P. D., Weiss, R. M., Wehrens, X. H. T., Song, L. S., ... Anderson, M. E. (2013). Oxidized Ca2+/Calmodulin-Dependent Protein Kinase II Triggers Atrial Fibrillation. Circulation, 128(16), 1748-1757. https://doi.org/10.1161/CIRCULATIONAHA.113.003313