Journal
CIRCULATION RESEARCH
Volume 92, Issue 8, Pages 904-911Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000069685.20258.F1
Keywords
calcium; Ca2+/calmodulin-dependent protein kinase II; sarcoplasmic reticulum; ryanodine receptor; heart
Funding
- NHLBI NIH HHS [HL-28143, HL-46345, HL-64724, HL-30077] Funding Source: Medline
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Ca2+/calmodulin-dependentprotein kinase II (CaMKII) delta is the predominant cardiac isoform, and the delta(C) splice variant is cytoplasmic. We overexpressed CaMKIIdelta(C) in mouse heart and observed dilated heart failure and altered myocyte Ca2+ regulation in 3-month-old CaMKIIdelta(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, [Ca2+](i) transient amplitude, and diastolic [Ca2+](i) were all reduced by approximate to50% in TG versus WT. This is explained by >50% reduction in SR Ca2+ content in TG versus WT. Peak Ca2+ current (I-Ca) was slightly increased, and action potential duration was prolonged in TG versus WT. Despite lower SR Ca2+ load and diastolic [Ca2+](i), fractional SR Ca2+ release was increased and resting spontaneous SR Ca2+ release events (Ca2+ sparks) were doubled in frequency in TG versus WT (with prolonged width and duration, but lower amplitude). Enhanced Ca2+ spark frequency was also seen in TG at 4 weeks (before heart failure onset). Acute CaMKII inhibition normalized Ca2+ spark frequency and I-Ca, consistent with direct CaMKII activation of ryanodine receptors (and I-Ca) in TG. The rate of [Ca2+](i) decline during caffeine exposure was faster in TG, indicating enhanced Na+-Ca2+ exchange function (consistent with protein expression measurements). Enhanced diastolic SR Ca2+ leak (via sparks), reduced SR Ca2+-ATPase expression, and increased Na+-Ca2+ exchanger explain the reduced diastolic [Ca2+](i) and SR Ca2+ content in TG. We conclude that CaMKIIdelta(C) overexpression causes acute modulation of excitation-contraction coupling, which contributes to heart failure.
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