Transgenic CaMKIIδc overexpression uniquely alters cardiac myocyte Ca2+ handling: Reduced SR Ca2+ load and activated SR Ca2+ release

Lars S. Maier, Tong Zhang, Lu Chen, Jaime DeSantiago, Joan Heller Brown, Donald M Bers

Research output: Contribution to journalArticle

344 Scopus citations

Abstract

Ca2+/calmodulin-dependent protein kinase II (CaMKII) δ is the predominant cardiac isoform, and the δC splice variant is cytoplasmic. We overexpressed CaMKIIδC in mouse heart and observed dilated heart failure and altered myocyte Ca2+ regulation in 3-month-old CaMKIIδC 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 ≈50% in TG versus WT. This is explained by >50% reduction in SR Ca2+ content in TG versus WT. Peak Ca2+ current (ICa) 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 ICa, consistent with direct CaMKII activation of ryanodine receptors (and ICa) 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 CaMKIIδC overexpression causes acute modulation of excitation-contraction coupling, which contributes to heart failure.

Original languageEnglish (US)
Pages (from-to)904-911
Number of pages8
JournalCirculation Research
Volume92
Issue number8
DOIs
StatePublished - May 2 2003
Externally publishedYes

Keywords

  • Ca/calmodulin-dependent protein kinase II
  • Calcium
  • Heart
  • Ryanodine receptor
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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