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


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.

SUBMITTER: Wang Q 

PROVIDER: S-EPMC5903581 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Oxidized CaMKII (Ca<sup>2+</sup>/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy.

Wang Qiongling Q   Quick Ann P AP   Cao Shuyi S   Reynolds Julia J   Chiang David Y DY   Beavers David D   Li Na N   Wang Guoliang G   Rodney George G GG   Anderson Mark E ME   Wehrens Xander H T XHT  

Circulation. Arrhythmia and electrophysiology 20180401 4


<h4>Background</h4>Duchenne muscular dystrophy patients are prone to ventricular arrhythmias, which may be caused by abnormal calcium (Ca<sup>2+</sup>) homeostasis and elevated reactive oxygen species. CaMKII (Ca<sup>2+</sup>/calmodulin-dependent protein kinase II) is vital for normal Ca<sup>2+</sup> homeostasis, but excessive CaMKII activity contributes to abnormal Ca<sup>2+</sup> homeostasis and arrhythmias in cardiomyocytes. Reactive oxygen species induce CaMKII to become autonomously active.  ...[more]

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