Overexpression of CaMKIIδc in RyR2 R4496C+/- knock-in mice leads to altered intracellular Ca 2+ handling and increased mortality

Nataliya Dybkova, Simon Sedej, Carlo Napolitano, Stefan Neef, Adam G. Rokita, Mark Hnlich, Joan Heller Brown, Jens Kockskmper, Silvia G. Priori, Burkert Pieske, Lars S. Maier

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives We investigated whether increased Ca 2+/calmodulin- dependent kinase II (CaMKII) activity aggravates defective excitation- contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2). Background RyR2 dysfunction is associated with arrhythmic events in inherited and acquired cardiac disease. Methods CaMKIIδc transgenic mice were crossbred with RyR2 R4496C+/- knock-in mice. Results Heart weight-to-body weight ratio in CaMKIIδc/RyR2 R4496C 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/RyR2 R4496C and CaMKIIδc mice. Sarcoplasmic reticulum Ca 2+ content in isolated myocytes was decreased to a similar extent in CaMKIIδc/RyR2 R4496C and CaMKIIδc mice. However, relaxation parameters and Ca 2+ decay at 1 Hz were prolonged significantly in CaMKIIδc mice versus CaMKIIδc/RyR2 R4496C mice. Sarcoplasmic reticulum Ca 2+ spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca 2+ leak in CaMKIIδc/RyR2 R4496C versus CaMKIIδc myocytes (p <0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKIIδc/ RyR2 R4496C versus CaMKIIδc mice. Increased arrhythmias in vivo (67% vs. 25%; p <0.05) may explain the increased mortality in CaMKIIδc/RyR2 R4496C mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIδc, p <0.05) after 14 weeks. Conclusions CaMKIIδc overexpression in RyR2 R4496C+/- knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor.

Original languageEnglish
Pages (from-to)469-479
Number of pages11
JournalJournal of the American College of Cardiology
Volume57
Issue number4
DOIs
Publication statusPublished - Jan 25 2011

Keywords

  • Ca /calmodulin-dependent kinase II
  • CaMKII
  • catecholaminergic polymorphic ventricular tachycardia
  • CPVT
  • DAD
  • delayed afterdepolarization
  • FDHM
  • full-duration half-maximum
  • full-width half-maximum
  • FWHM
  • heart failure
  • HF
  • I
  • L-type Ca current
  • Na /Ca exchanger
  • NCX
  • phospholamban
  • PLB
  • ryanodine receptors
  • RyR2
  • sarcoplasmic reticulum
  • sarcoplasmic reticulum Ca ATPase
  • SERCA2
  • SR
  • wild-type
  • WT

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Overexpression of CaMKIIδc in RyR2 R4496C+/- knock-in mice leads to altered intracellular Ca 2+ handling and increased mortality'. Together they form a unique fingerprint.

Cite this