Phospholamban Ablation Rescues Sarcoplasmic Reticulum Ca 2+ Handling but Exacerbates Cardiac Dysfunction in CaMKIIδ C Transgenic Mice

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Abstract
Rationale : We previously showed that transgenic mice expressing Ca 2+ /calmodulin-dependent protein kinase II δ C (CaMKII-TG) develop dilated cardiomyopathy associated with increased ryanodine receptors (RyR2) phosphorylation, enhanced sarcoplasmic reticulum (SR) Ca 2+ leak and lowering of SR Ca 2+ load. We hypothesized that phospholamban (PLN) ablation would restore SR Ca 2+ 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 CaMKIIδ C 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 Ca 2+ load and twitch Ca 2+ 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 Ca 2+ sparks and leak were significantly increased, presumably because of the combined effects of restored SR Ca 2+ load and RyR2 phosphorylation. Mitochondrial Ca 2+ loading was increased in cardiomyocytes from KO/TG versus WT or CaMKII-TG mice and this was dependent on elevated SR Ca 2+ sparks. Cardiomyocytes from KO/TG showed poor viability, improved by inhibiting SR Ca 2+ release and mitochondrial Ca 2+ loading. Conclusions : Normalizing cardiomyocyte SR Ca 2+ loading in the face of elevated CaMKII and RyR2 phosphorylation leads to enhanced SR Ca 2+ leak and mitochondrial Ca 2+ elevation, associated with exacerbated cell death, heart failure and mortality.

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