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 Anderson, Thomas J. Hund, Peter J. Mohler

Research output: Contribution to journalArticle

Abstract

BACKGROUND: 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. OBJECTIVE: To test the relationship between myocyte kinase/phosphatase imbalance and cellular and whole animal arrhythmia phenotypes associated with ankyrin-B cardiac syndrome. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)2034-2041
Number of pages8
JournalHeart Rhythm
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2012
Externally publishedYes

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Keywords

  • Ankyrin
  • Arrhythmia
  • CaMKII
  • Ryanodine receptor
  • Spectrin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Degrande, S., Nixon, D., Koval, O., Curran, J. W., Wright, P., Wang, Q., ... Mohler, P. J. (2012). CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome. Heart Rhythm, 9(12), 2034-2041. https://doi.org/10.1016/j.hrthm.2012.08.026