CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome

Sean DeGrande; Derek Nixon; Olha Koval; Jerald W. Curran; Patrick Wright; Qiongling Wang; Farshid Kashef; David Chiang; Na Li; Xander H.T. Wehrens; Mark E. Anderson; Thomas J. Hund; Peter J. Mohler

doi:10.1016/j.hrthm.2012.08.026

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CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome

Journal article

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CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome

Sean DeGrande, Derek Nixon, Olha Koval, Jerald W. Curran, Patrick Wright, Qiongling Wang, Farshid Kashef, David Chiang, Na Li, Xander H.T. Wehrens, …

Heart rhythm, Vol.9(12), pp.2034-2041

12/2012

DOI: 10.1016/j.hrthm.2012.08.026

PMCID: PMC3630478

PMID: 23059182

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https://www.ncbi.nlm.nih.gov/pmc/articles/3630478View

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Abstract

Cardiovascular disease is a leading cause of death worldwide. Arrhythmias are associated with significant morbidity and mortality related to cardiovascular disease. Recent work illustrates that many cardiac arrhythmias are initiated by a pathologic imbalance between kinase and phosphatase activities in excitable cardiomyocytes. To test the relationship between myocyte kinase/phosphatase imbalance and cellular and whole animal arrhythmia phenotypes associated with ankyrin-B cardiac syndrome. By using a combination of biochemical, electrophysiological, and in vivo approaches, we tested the ability of calcium/calmodulin-dependent kinase (CaMKII) inhibition to rescue imbalance in kinase/phosphatase pathways associated with human ankyrin-B-associated cardiac arrhythmia. The cardiac ryanodine receptor (RyR2), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B+/− heart. Notably, RyR2 dysregulation is rescued in myocytes from ankyrin-B+/− mice overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant RyR2 open probability observed in ankyrin-B+/− hearts is normalized by treatment with the CaMKII inhibitor KN-93. CaMKII inhibition is sufficient to rescue abnormalities in ankyrin-B+/− myocyte electrical dysfunction including cellular afterdepolarizations, and significantly blunts whole animal cardiac arrhythmias and sudden death in response to elevated sympathetic tone. These findings illustrate the complexity of the molecular components involved in human arrhythmia and define regulatory elements of the ankyrin-B pathway in pathophysiology. Furthermore, the findings illustrate the potential impact of CaMKII inhibition in the treatment of a congenital form of human cardiac arrhythmia.

Ankyrin

Arrhythmia

CaMKII

Ryanodine receptor

Spectrin

Details

Title: Subtitle: CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome
Creators: Sean DeGrande - The Ohio State University Wexner Medical Center
Derek Nixon - The Ohio State University Wexner Medical Center
Olha Koval - University of Iowa
Jerald W. Curran - The Ohio State University Wexner Medical Center
Patrick Wright - The Ohio State University Wexner Medical Center
Qiongling Wang - Baylor College of Medicine
Farshid Kashef - The Ohio State University Wexner Medical Center
David Chiang - Baylor College of Medicine
Na Li - Baylor College of Medicine
Xander H.T. Wehrens - Baylor College of Medicine
Mark E. Anderson - Roy J. and Lucille A. Carver College of Medicine
Thomas J. Hund - The Ohio State University
Peter J. Mohler - The Ohio State University Wexner Medical Center
Resource Type: Journal article
Publication Details: Heart rhythm, Vol.9(12), pp.2034-2041
DOI: 10.1016/j.hrthm.2012.08.026
PMID: 23059182
PMCID: PMC3630478
NLM abbreviation: Heart Rhythm
ISSN: 1547-5271
eISSN: 1556-3871
Publisher: Elsevier Inc
Language: English
Date published: 12/2012
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984359680902771

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