CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome.
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 (RyR(2)), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B(+/-) heart. Notably, RyR(2) dysregulation is rescued in myocytes from ankyrin-B(+/-) mice overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant RyR(2) 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.
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
Sean
S
DeGrande
Derek
D
Nixon
Olha
O
Koval
Jerald W
JW
Curran
Patrick
P
Wright
Qiongling
Q
Wang
Farshid
F
Kashef
David
D
Chiang
Na
N
Li
Xander H T
XH
Wehrens
Mark E
ME
Anderson
Thomas J
TJ
Hund
Peter J
PJ
Mohler
D000818:Animals; D017487:Ankyrins / Q000172:deficiency / Q000235:genetics*; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
C498994:ANK2 protein, human; D017487:Ankyrins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2