Transgenic CaMKIIδ C Overexpression Uniquely Alters Cardiac Myocyte Ca 2+ Handling

Abstract

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) δ is the predominant cardiac isoform, and the δ C splice variant is cytoplasmic. We overexpressed CaMKIIδ C in mouse heart and observed dilated heart failure and altered myocyte Ca 2+ regulation in 3-month-old CaMKIIδ C transgenic mice (TG) versus wild-type littermates (WT). Heart/body weight ratio and cardiomyocyte size were increased about 2-fold in TG versus WT. At 1 Hz, twitch shortening, [Ca 2+ ] i transient amplitude, and diastolic [Ca 2+ ] i were all reduced by ≈50% in TG versus WT. This is explained by >50% reduction in SR Ca 2+ content in TG versus WT. Peak Ca 2+ current ( I Ca ) was slightly increased, and action potential duration was prolonged in TG versus WT. Despite lower SR Ca 2+ load and diastolic [Ca 2+ ] i , fractional SR Ca 2+ release was increased and resting spontaneous SR Ca 2+ release events (Ca 2+ sparks) were doubled in frequency in TG versus WT (with prolonged width and duration, but lower amplitude). Enhanced Ca 2+ spark frequency was also seen in TG at 4 weeks (before heart failure onset). Acute CaMKII inhibition normalized Ca 2+ spark frequency and I Ca , consistent with direct CaMKII activation of ryanodine receptors (and I Ca ) in TG. The rate of [Ca 2+ ] i decline during caffeine exposure was faster in TG, indicating enhanced Na + -Ca 2+ exchange function (consistent with protein expression measurements). Enhanced diastolic SR Ca 2+ leak (via sparks), reduced SR Ca 2+ -ATPase expression, and increased Na + -Ca 2+ exchanger explain the reduced diastolic [Ca 2+ ] i and SR Ca 2+ content in TG. We conclude that CaMKIIδ C overexpression causes acute modulation of excitation-contraction coupling, which contributes to heart failure.