title: Oxidized Ca(2+)/calmodulin-dependent protein kinase II triggers atrial fibrillation.
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(2+)/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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine and Cardiovascular Research Center, Carver College of Medicine (A.P., A.G.R., X.G., B.C., O.M.K., Z.G., E.D.L., H.S., A.C.B., R.N.E.-A., P.D.S., R.M.W., L.-S.S., M.E.A.), Department of Obstetrics and Gynecology (B.Y.), and Department of Molecular Physiology and Biophysics (M.E.A.), University of Iowa, Iowa City; Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany, and Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); Cardiology and Pneumology, German Heart Center, University Hospital Goettingen, Goettingen, Germany (S.N., T.S., L.S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (N.L., X.H.T.W.).
authors.forename: Anil
authors.initials: A
authors.lastname: Purohit
authors.forename: Adam G
authors.initials: AG
authors.lastname: Rokita
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Thomas
authors.initials: T
authors.lastname: Sowa
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Luczak
authors.forename: Hrafnhildur
authors.initials: H
authors.lastname: Stefansdottir
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Behunin
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Ramzi N
authors.initials: RN
authors.lastname: El-Accaoui
authors.forename: Baoli
authors.initials: B
authors.lastname: Yang
authors.forename: Paari Dominic
authors.initials: PD
authors.lastname: Swaminathan
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000368:Aged; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D020013:Calcium Signaling / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005260:Female; D006329:Heart Conduction System / Q000378:metabolism*; D006801:Humans; D008297:Male; D051150:Methionine Sulfoxide Reductases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D000804:Angiotensin II; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; C517660:CAMK2D protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517673:Camk2d protein, mouse
keywords: angiotensin II; arrhythmias, cardiac; atrial fibrillation; calcium-calmodulin-dependent protein kinase type II; reactive oxygen species
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