Overexpression of CaMKIIδc in RyR2R4496C+/− Knock-In Mice Leads to Altered Intracellular Ca2+ Handling and Increased Mortality

Objectives estigated whether increased Ca2+/calmodulin-dependent kinase II (CaMKII) activity aggravates defective excitation-contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2). ound ysfunction is associated with arrhythmic events in inherited and acquired cardiac disease. s δc transgenic mice were crossbred with RyR2R4496C+/− knock-in mice. s weight-to-body weight ratio in CaMKIIδc/RyR2R4496C and CaMKIIδc mice was similarly increased approximately 3-fold versus wild-type mice (p < 0.05). Echocardiographic data showed comparable cardiac dilation and impaired contractility in CaMKIIδc/RyR2R4496C and CaMKIIδc mice. Sarcoplasmic reticulum Ca2+ content in isolated myocytes was decreased to a similar extent in CaMKIIδc/RyR2R4496C and CaMKIIδc mice. However, relaxation parameters and Ca2+ decay at 1 Hz were prolonged significantly in CaMKIIδc mice versus CaMKIIδc/RyR2R4496C mice. Sarcoplasmic reticulum Ca2+ spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca2+ leak in CaMKIIδc/RyR2R4496C versus CaMKIIδc myocytes (p < 0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKIIδc/RyR2R4496C versus CaMKIIδc mice. Increased arrhythmias in vivo (67% vs. 25%; p < 0.05) may explain the increased mortality in CaMKIIδc/RyR2R4496C mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIδc, p < 0.05) after 14 weeks. sions δc overexpression in RyR2R4496C+/− knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor.