Transgenic CaMKII {delta} C overexpression uniquely alters cardiac myocyte Ca2+ handling: reduced SR Ca2+ load and activated SR Ca2+ release (original) (raw)

Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) ␦ is the predominant cardiac isoform, and the ␦ C splice variant is cytoplasmic. We overexpressed CaMKII␦ C in mouse heart and observed dilated heart failure and altered myocyte Ca 2ϩ regulation in 3-month-old CaMKII␦ 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 2ϩ ] i transient amplitude, and diastolic [Ca 2ϩ ] i were all reduced by Ϸ50% in TG versus WT. This is explained by Ͼ50% reduction in SR Ca 2ϩ content in TG versus WT. Peak Ca 2ϩ current (I Ca ) was slightly increased, and action potential duration was prolonged in TG versus WT. Despite lower SR Ca 2ϩ load and diastolic [Ca 2ϩ ] i , fractional SR Ca 2ϩ release was increased and resting spontaneous SR Ca 2ϩ release events (Ca 2ϩ sparks) were doubled in frequency in TG versus WT (with prolonged width and duration, but lower amplitude). Enhanced Ca 2ϩ spark frequency was also seen in TG at 4 weeks (before heart failure onset). Acute CaMKII inhibition normalized Ca 2ϩ spark frequency and I Ca , consistent with direct CaMKII activation of ryanodine receptors (and I Ca ) in TG. The rate of [Ca 2ϩ ] i decline during caffeine exposure was faster in TG, indicating enhanced Na ϩ -Ca 2ϩ exchange function (consistent with protein expression measurements). Enhanced diastolic SR Ca 2ϩ leak (via sparks), reduced SR Ca 2ϩ -ATPase expression, and increased Na ϩ -Ca 2ϩ exchanger explain the reduced diastolic [Ca 2ϩ ] i and SR Ca 2ϩ content in TG. We conclude that CaMKII␦ C overexpression causes acute modulation of excitation-contraction coupling, which contributes to heart failure. (Circ Res. 2003;92:904-911.) Key Words: calcium Ⅲ Ca 2ϩ /calmodulin-dependent protein kinase II Ⅲ sarcoplasmic reticulum Ⅲ ryanodine receptor Ⅲ heart Original