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Oxidized CaMKII (Ca 2+ /Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy
- Source :
- Circulation: Arrhythmia and Electrophysiology. 11
- Publication Year :
- 2018
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2018.
-
Abstract
- Background: Duchenne muscular dystrophy patients are prone to ventricular arrhythmias, which may be caused by abnormal calcium (Ca 2+ ) homeostasis and elevated reactive oxygen species. CaMKII (Ca 2+ /calmodulin-dependent protein kinase II) is vital for normal Ca 2+ homeostasis, but excessive CaMKII activity contributes to abnormal Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ homeostasis, and rescued inducible ventricular arrhythmias in mdx mice. Conclusions: Inhibition of reactive oxygen species or ox-CaMKII protects against proarrhythmic intracellular Ca 2+ handling and prevents ventricular arrhythmia in a mouse model of Duchenne muscular dystrophy.
- Subjects :
- 0301 basic medicine
mdx mouse
medicine.medical_specialty
Duchenne muscular dystrophy
030204 cardiovascular system & hematology
Ventricular tachycardia
03 medical and health sciences
0302 clinical medicine
Calcium imaging
Physiology (medical)
Internal medicine
Ca2+/calmodulin-dependent protein kinase
medicine
chemistry.chemical_classification
Reactive oxygen species
NADPH oxidase
biology
business.industry
medicine.disease
030104 developmental biology
Endocrinology
chemistry
cardiovascular system
biology.protein
Cardiology and Cardiovascular Medicine
business
Homeostasis
Subjects
Details
- ISSN :
- 19413084 and 19413149
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Circulation: Arrhythmia and Electrophysiology
- Accession number :
- edsair.doi...........6c1f584af92e83ca3ca438ece6de2eb7