Abstract 5406: The Role Of Calstabin2 (fkbp12.6) In Progression Of Ischemic Heart Failure With Different Alterations In Ca2+ Cycling Proteins
As an important regulator of Ryanodine receptor (RyR) in the heart, calstabin2 (FKBP12.6) binding to RyR2 has been shown to stabilize the channel by inhibiting diastolic Ca2+ leak from sarcoplasmic reticulum (SR) in heart failure (HF) and sudden cardiac death (SCD). Using different genetic mouse models, we tested the hypothesis that calstabin2 binding to RyR2 is necessary for maintaining the normal cardiac function and preventing SCD in ischemic HF.
METHODS AND RESULTS: We first used calstabin2 knock out (KO) crossed with phospholamban KO mice (CLN2−/−;PLN−/−). After myocardial infarction (MI) induced by proximal left descending artery ligation, CLN2−/−;PLN−/− mice showed a significantly higher mortality rate within 7-days post surgery compared to WT and CLN2−/− mice (63.27%, n=49; 7.27%, n=55 and 12%, n=25 , respectively; P<0.05 vs. WT and CLN2−/−). The cardiac functions of these crossed mice measured by echocardiography were similar to WT at week-1 after acute MI but significantly higher than CLN2−/− mice (EF 49.27%±2.77%, n=19 and 50.32%±1.54%, n=47, vs. 37.59%±2.2%, n=23; P<0.05). To further explore the cause of high mortality, we continuously recorded ECG with telemetry implantation after acute MI. Among 7 CLN2−/−;PLN−/−mice, six died within 7 days after MI comparing to 1/5 died in WT group. All mortalities in CLN2−/−;PLN−/− mice were arrhythmia related and 4/6 (66.67%) died of ventricular fibrillation. Since we have shown that RyR2-S2808A mutation protects mice from HF after acute MI previously, we tested the cardiac function and mortality in RyR2-S2808A+/+X CLN2−/− mice subjected to acute MI. Comparing to WT, these mice showed a similar mortality 28-days after surgery (12.5%, n=24 vs. 20%, n=25; P=NS) but a significantly higher EF (54.2%±1.59%, n=24 vs. 44.19%±2.80%, n=25 , P<0.05) comparable to that of RyR2-S2808A mice as we previous reported.
CONCLUSION: Calstabin2 binding to RyR2 is important for maintaining cardiac function in HF and enhanced Ca2+ reuptake due to PLN deficiency in absence of calstabin2 increased mortality after acute MI due to increased prevalence of SCD. The protective effect of RyR2-S2808A in HF confirms that both RyR2-PKA hyperphosphorylation and calstabin2 dissociation contribute to HF progression after acute MI.