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

被引：41

作者：

Wang, Qiongling ^{[1
]}

Quick, Ann P. ^{[1
]}

Cao, Shuyi ^{[1
]}

Reynolds, Julia ^{[1
]}

Chiang, David Y. ^{[1
,5
]}

Beavers, David ^{[1
,6
]}

Li, Na ^{[1
,2
]}

Wang, Guoliang ^{[1
]}

Rodney, George G. ^{[1
]}

Anderson, Mark E. ^{[7
]}

Wehrens, Xander H. T. ^{[1
,2
,3
,4
]}

机构：

[1] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA

[2] Baylor Coll Med, Dept Med Cardiol, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Pediat Cardiol, Houston, TX 77030 USA

[4] Baylor Coll Med, Ctr Space Med, Houston, TX 77030 USA

[5] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA

[6] Duke Univ, Sch Med, Durham, NC USA

[7] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

来源：

CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY | 2018年 / 11卷 / 04期

基金：

美国国家卫生研究院;

关键词：

action potential; arrhythmia; calcium/calmodulin-dependent protein kinase II; Duchenne muscular dystrophy; reactive oxygen species; HEART-FAILURE; PHOSPHORYLATION; CARDIOMYOPATHY; CONTRIBUTES; DYSFUNCTION; PROGRESSION; INHIBITION; DISEASE; MICE;

D O I：

10.1161/CIRCEP.117.005682

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页数：10

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