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Circulation ; 128(16): 1748-57, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24030498

RESUMO

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. 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.


Assuntos
Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Sistema de Condução Cardíaco/metabolismo , Idoso , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Fibrilação Atrial/prevenção & controle , Sinalização do Cálcio/fisiologia , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Feminino , Humanos , Masculino , Metionina Sulfóxido Redutases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Oxirredução , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
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