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

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 We tested the relationship between myocyte kinase/phosphatase imbalance and cellular and whole animal arrhythmia phenotypes associated with ankyrin-B cardiac syndrome. Methods Using a combination of biochemical, electrophysiological, and in vivo approaches, we tested the ability of 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.

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

“…This may indicate differential functions of B56α depending on cellular compartment that may be facilitated by the phosphorylation of B56α at Ser41 (modifies PP2A-C-B56α affinity) [43,76]. B56α has also been implicated in the pathophysiology of “Ankyrin-B Syndrome”, as the loss of ankyrin-B function, essential to B56α localization, may lead to altered RyR2 phosphorylation and arrhythmia [43,77]. …”

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

“…Recently, work from our group and others has provided functional data that link dysfunction in local PP2A subunit targeting and activity with highly penetrant and potentially fatal human cardiac arrhythmia (27)(28)(29)(30)(31)(32)(33)(34)(35). These clinical and translational findings have raised fundamental questions regarding the scope and regulation of PP2A subunit in human heart and in cardiovascular disease.…”

Role of CaMKII in cardiac arrhythmias

“…Aside from acquired disease, CaMKII dysregulation contributes to pathology in a number of inherited arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, long QT type 3, ankyrin-B syndrome (long QT type 4), and Timothy syndrome (long QT type 8) [33–36]. These findings raise the question of when/if will a therapeutic agent be available that specifically targets CaM-KII?…”