Phospholamban ablation rescues sarcoplasmic reticulum ca2+ handling but exacerbates cardiac dysfunction in CaMKIIδC transgenic mice

Tong Zhang, Tao Guo, Shikha Mishra, Nancy D. Dalton, Evangelia G. Kranias, Kirk L. Peterson, Donald M Bers, Joan Heller Brown

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Rationale: We previously showed that transgenic mice expressing Ca 2+/calmodulin-dependent protein kinase II δC (CaMKII-TG) develop dilated cardiomyopathy associated with increased ryanodine receptors (RyR2) phosphorylation, enhanced sarcoplasmic reticulum (SR) Ca 2+ leak and lowering of SR Ca2+ load. We hypothesized that phospholamban (PLN) ablation would restore SR Ca load and prevent the decreased ventricular contractility, dilation and mortality seen in CaMKII-TG. Objective: Our objectives were to generate CaMKII-TG mice lacking PLN, determine whether the maladaptive effects of cardiac CaMKIIδC expression were corrected, and establish the mechanistic basis for these changes. Methods and Results: CaMKII-TG were crossed with PLN knockout (PLN-KO) mice to generate KO/TG mice. Myocytes from wild type (WT), CaMKII-TG, PLN-KO and KO/TG were compared. The decreased SR Ca2+ load and twitch Ca2+ transients seen in CaMKII-TG were normalized in KO/TG. Surprisingly the heart failure phenotype was exacerbated, as indicated by increased left ventricular dilation, decreased ventricular function, increased apoptosis and greater mortality. In KO/TG myocytes SR Ca2+ sparks and leak were significantly increased, presumably because of the combined effects of restored SR Ca2+ load and RyR2 phosphorylation. Mitochondrial Ca2+ loading was increased in cardiomyocytes from KO/TG versus WT or CaMKII-TG mice and this was dependent on elevated SR Ca2+ sparks. Cardiomyocytes from KO/TG showed poor viability, improved by inhibiting SR Ca2+ release and mitochondrial Ca2+ loading. Conclusions: Normalizing cardiomyocyte SR Ca2+ loading in the face of elevated CaMKII and RyR2 phosphorylation leads to enhanced SR Ca2+ leak and mitochondrial Ca2+ elevation, associated with exacerbated cell death, heart failure and mortality.

Original languageEnglish (US)
Pages (from-to)354-362
Number of pages9
JournalCirculation Research
Volume106
Issue number2
DOIs
StatePublished - Feb 2010

Keywords

  • Ca/calmodulin-dependent protein kinase II
  • Calcium
  • Heart failure
  • Phospholamban

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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