Abstract
Diastolic calcium leak through the cardiac ryanodine receptor (RyR2) is associated with numerous cardiovascular diseases, including myocardial infarction (MI) induced heart failure and electrical dysfunction. Protein kinase CK2 (CK2) phosphorylates RyR2 in physiological conditions and its absence is associated with increased calcium leak. MIs provide a cellular environment in which CK2 activity is suppressed, therefore providing a novel link between MI and increased pathological calcium leak. The aim of the present study was to evaluate whether retention of CK2 phosphorylation of RyR2 postMI was protective against calcium leak related complication such as heart failure and electrical dysfunction.
Mouse models with modified RyR2 residues that mimic (S2692/3D) or prevent (S2692/3A) CK2-associated phosphorylation were used and compared to wildtype controls. Mice underwent surgical induction of either permanent ligation (PL) or ischaemia reperfusion (IR) MIs. Echocardiography was used to determine structural and functional parameters, and electrocardiography (ECG) was used to detect electrical activity.
PL resulted in a global reduction in cardiac function, similar across groups. Pathological remodelling was also observed but had a trend of being more prominent within the mice with retained CK2 phosphorylation (S2692/3D). IR resulted in lesser functional and structural changes that were more prominent within the reduced CK2 phosphorylation (S2692/3A) group. Electrical changes also occurred post-MI indicating that greater cardiovascular disease progression occurred within the retained phosphorylation group in PL and the reduced phosphorylation group in the IR.
The results show that CK2 mediated phosphorylation of RyR2 is important in the regulation of heart failure and electrical activity post-MI. However, this effect was shown to be dependent on revascularisation, with PL and IR MIs having different changes to cardiac structure, function, and electrical activity based on CK2 phosphorylation.