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 language | English (US) |
|---|---|
| Pages (from-to) | 354-362 |
| Number of pages | 9 |
| Journal | Circulation Research |
| Volume | 106 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2010 |
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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 journal › Article
}
TY - JOUR
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
Y1 - 2010/2
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
UR - http://www.scopus.com/inward/record.url?scp=76349084460&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=76349084460&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.109.207423
DO - 10.1161/CIRCRESAHA.109.207423
M3 - Article
C2 - 19959778
AN - SCOPUS:76349084460
VL - 106
SP - 354
EP - 362
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 2
ER -