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

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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

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Sarcoplasmic Reticulum
Transgenic Mice
Ryanodine Receptor Calcium Release Channel
Cardiac Myocytes
Phosphorylation
Muscle Cells
Mortality
Dilatation
Heart Failure
phospholamban
Calcium-Calmodulin-Dependent Protein Kinases
Ventricular Function
Dilated Cardiomyopathy
Knockout Mice
Protein Kinase C
Cell Death
Apoptosis
Phenotype

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Phospholamban ablation rescues sarcoplasmic reticulum ca2+ handling but exacerbates cardiac dysfunction in CaMKIIδC transgenic mice. / Zhang, Tong; Guo, Tao; Mishra, Shikha; Dalton, Nancy D.; Kranias, Evangelia G.; Peterson, Kirk L.; Bers, Donald M; Brown, Joan Heller.

In: Circulation Research, Vol. 106, No. 2, 02.2010, p. 354-362.

Research output: Contribution to journalArticle

Zhang, Tong ; Guo, Tao ; Mishra, Shikha ; Dalton, Nancy D. ; Kranias, Evangelia G. ; Peterson, Kirk L. ; Bers, Donald M ; Brown, Joan Heller. / Phospholamban ablation rescues sarcoplasmic reticulum ca2+ handling but exacerbates cardiac dysfunction in CaMKIIδC transgenic mice. In: Circulation Research. 2010 ; Vol. 106, No. 2. pp. 354-362.
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T1 - Phospholamban ablation rescues sarcoplasmic reticulum ca2+ handling but exacerbates cardiac dysfunction in CaMKIIδC transgenic mice

AU - Zhang, Tong

AU - Guo, Tao

AU - Mishra, Shikha

AU - Dalton, Nancy D.

AU - Kranias, Evangelia G.

AU - Peterson, Kirk L.

AU - Bers, Donald M

AU - Brown, Joan Heller

PY - 2010/2

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N2 - 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.

AB - 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.

KW - Ca/calmodulin-dependent protein kinase II

KW - Calcium

KW - Heart failure

KW - Phospholamban

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