Abstract
Diastolic calcium leak through the cardiac ryanodine receptor (RyR2) is associated with numerous cardiovascular diseases, including myocardial infarction (MI) induced heart failure and arrhythmia. RyR2 regulation is mediated by several factors, one being protein kinase CK2 (CK2). In physiological conditions RyR2 is phosphorylated by CK2 and loss of this phosphorylation results in increased diastolic calcium leak. MIs provide a cellular environment in which CK2 activity is suppressed. Therefore, phosphorylation of RyR2 by CK2 is potentially downregulated following an MI, increasing pathological calcium leak, pushing the heart into failure and arrhythmias. The aim of this study was to evaluate whether retention of CK2 phosphorylation of RyR2 post-MI is protective against complications such as heart failure and arrhythmia.
Mouse models with modified RyR2 residues that mimic (SD) or prevent (SA) CK2-associated phosphorylation were used and compared to wildtype controls. Mice underwent surgical induction of either permanent ligation (PL) (SD: n = 6, Wildtype: n = 6) or ischaemia reperfusion (IR) (SD: n = 2, SA: n = 4, Wildtype: n = 6) MIs. Echocardiography was used to determine ejection fraction as a measure cardiac function, representing progression towards heart failure, and electrocardiography (ECGs) was used to detect arrhythmic activity.
PL led to a dramatic reduction in ejection fraction (Baseline: 80.4% +/- 0.63%, post-MI: 62.1% +/- 1.7%, P < 0.0001) which showed minimal difference between genotypes (1.5% +/- 3.1%, P = 0.6334). IR also resulted in the reduction of ejection fraction (Baseline: 81.2% +/- 0.8%, post-MI: 65.1% +/- 2.3%, P < 0.0001) however, SA had a more severe impairment compared to wildtype mice (4.5% +/- 1.5%, P = 0.0182). Changes in arrhythmic activity were not seen between genotypes in either MI environment (P > 0.05).
These results indicate that CK2-mediated phosphorylation of RyR2 is important in regulating MI-induced heart failure. This effect is dependent on the type of MI, with PL and IR revealing different changes in cardiac function based on CK2 phosphorylation.