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Circ Arrhythm Electrophysiol. 2018 Apr;11(4):e005682. doi: 10.1161/CIRCEP.117.005682.

Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy.

Author information

1
Department of Molecular Physiology and Biophysics (Q.W., A.P.Q., S.C., J.R., D.Y.C., D.B., N.L., G.W., G.G.R., X.H.T.W.), Department of Medicine (Cardiology) (N.L., X.H.T.W.), Department of Pediatrics (Cardiology) (X.H.T.W.), and Center for Space Medicine (X.H.T.W.), Baylor College of Medicine, Houston, TX. Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.Y.C.). Duke University School of Medicine, Durham, NC (D.B.). Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.E.A.).
2
Department of Molecular Physiology and Biophysics (Q.W., A.P.Q., S.C., J.R., D.Y.C., D.B., N.L., G.W., G.G.R., X.H.T.W.), Department of Medicine (Cardiology) (N.L., X.H.T.W.), Department of Pediatrics (Cardiology) (X.H.T.W.), and Center for Space Medicine (X.H.T.W.), Baylor College of Medicine, Houston, TX. Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.Y.C.). Duke University School of Medicine, Durham, NC (D.B.). Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (M.E.A.). wehrens@bcm.edu.

Abstract

BACKGROUND:

Duchenne muscular dystrophy patients are prone to ventricular arrhythmias, which may be caused by abnormal calcium (Ca2+) homeostasis and elevated reactive oxygen species. CaMKII (Ca2+/calmodulin-dependent protein kinase II) is vital for normal Ca2+ homeostasis, but excessive CaMKII activity contributes to abnormal Ca2+ homeostasis and arrhythmias in cardiomyocytes. Reactive oxygen species induce CaMKII to become autonomously active. We hypothesized that genetic inhibition of CaMKII oxidation (ox-CaMKII) in a mouse model of Duchenne muscular dystrophy can alleviate abnormal Ca2+ homeostasis, thus, preventing ventricular arrhythmia. The objective of this study was to test if selective loss of ox-CaMKII affects ventricular arrhythmias in the mdx mouse model of Duchenne muscular dystrophy.

METHODS AND RESULTS:

5-(6)-Chloromethyl-2,7-dichlorodihydrofluorescein diacetate staining revealed increased reactive oxygen species production in ventricular myocytes isolated from mdx mice, which coincides with elevated ventricular ox-CaMKII demonstrated by Western blotting. Genetic inhibition of ox-CaMKII by knockin replacement of the regulatory domain methionines with valines (MM-VV [CaMKII M281/282V]) prevented ventricular tachycardia in mdx mice. Confocal calcium imaging of ventricular myocytes isolated from mdx:MM-VV mice revealed normalization of intracellular Ca2+ release events compared with cardiomyocytes from mdx mice. Abnormal action potentials assessed by optical mapping in mdx mice were also alleviated by genetic inhibition of ox-CaMKII. Knockout of the NADPH oxidase regulatory subunit p47 phox normalized elevated ox-CaMKII, repaired intracellular Ca2+ homeostasis, and rescued inducible ventricular arrhythmias in mdx mice.

CONCLUSIONS:

Inhibition of reactive oxygen species or ox-CaMKII protects against proarrhythmic intracellular Ca2+ handling and prevents ventricular arrhythmia in a mouse model of Duchenne muscular dystrophy.

KEYWORDS:

Duchenne muscular dystrophy; action potential; arrhythmia; calcium/calmodulin-dependent protein kinase II; reactive oxygen species

PMID:
29654126
PMCID:
PMC5903581
[Available on 2019-04-01]
DOI:
10.1161/CIRCEP.117.005682

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