Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814
Mice with constitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D⁺<sup>/</sup>⁺) have increased propensity to arrhythmias under β-adrenergic stress conditions. Although abnormal Ca²⁺ release from the sarcoplasmic reticulum (SR) has been linked to arrhythmogenesis, the role played by...
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| Autores principales: | , , , , , , , , , , , , , , , |
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| Formato: | Articulo |
| Lenguaje: | Inglés |
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2016
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| Acceso en línea: | http://sedici.unlp.edu.ar/handle/10915/127243 |
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I19-R120-10915-127243 |
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dspace |
| institution |
Universidad Nacional de La Plata |
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I-19 |
| repository_str |
R-120 |
| collection |
SEDICI (UNLP) |
| language |
Inglés |
| topic |
Medicina mice pseudo-phosphorylation arrhythmias phospholamban ablation |
| spellingShingle |
Medicina mice pseudo-phosphorylation arrhythmias phospholamban ablation Mazzocchi, Gabriela Sommese, Leandro Matías Palomeque, Julieta Felice, Juan Ignacio Di Carlo, Mariano Nahuel Fainstein, D. González, P. N. Contreras, Paola Skapura, Darlene G. McCauley, Mark D. Lascano, Elena C. Negroni, Jorge A. Kranias, Evangelia G. Wehrens, Xander H. T. Valverde, Carlos Alfredo Mattiazzi, Alicia Ramona Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814 |
| topic_facet |
Medicina mice pseudo-phosphorylation arrhythmias phospholamban ablation |
| description |
Mice with constitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D⁺<sup>/</sup>⁺) have increased propensity to arrhythmias under β-adrenergic stress conditions. Although abnormal Ca²⁺ release from the sarcoplasmic reticulum (SR) has been linked to arrhythmogenesis, the role played by SR Ca²⁺ uptake remains controversial. We tested the hypothesis that an increase in SR Ca²⁺ uptake is able to rescue the increased arrhythmia propensity of S2814D⁺<sup>/</sup>⁺ mice. We generated phospholamban (PLN)-deficient/S2814D⁺<sup>/</sup>⁺ knock-in mice by crossing two colonies, S2814D⁺<sup>/</sup>⁺ and PLNKO mice (SD⁺<sup>/</sup>⁺/KO). SD⁺<sup>/</sup>⁺/KO myocytes exhibited both increased SR Ca²⁺ uptake seen in PLN knock-out (PLNKO) myocytes and diminished SR Ca²⁺ load (relative to PLNKO), a characteristic of S2814D⁺<sup>/</sup>⁺ myocytes. Ventricular arrhythmias evoked by catecholaminergic challenge (caffeine/adrenaline) in S2814D⁺<sup>/</sup>⁺ mice <i>in vivo</i> or programmed electric stimulation and high extracellular Ca²⁺ in S2814D⁺<sup>/</sup>⁻ hearts <i>ex vivo</i> were significantly diminished by PLN ablation. At the myocyte level, PLN ablation converted the arrhythmogenic Ca²⁺ waves evoked by high extracellular Ca²⁺ provocation in S2814D⁺<sup>/</sup>⁺ mice into non-propagated Ca²⁺ mini-waves on confocal microscopy. Myocyte Ca²⁺ waves, typical of S2814D⁺<sup>/</sup>⁺ mice, could be evoked in SD⁺<sup>/</sup>⁺/KO cells by partially inhibiting SERCA2a. A mathematical human myocyte model replicated these results and allowed for predicting the increase in SR Ca²⁺ uptake required to prevent the arrhythmias induced by a Ca²⁺-calmodulin-dependent protein kinase (CaMKII)-dependent leaky RyR2. Our results demonstrate that increasing SR Ca²⁺ uptake by PLN ablation can prevent the arrhythmic events triggered by SR Ca²⁺ leak due to CaMKII-dependent phosphorylation of the RyR2-S2814 site and underscore the benefits of increasing SERCA2a activity on SR Ca²⁺-triggered arrhythmias. |
| format |
Articulo Articulo |
| author |
Mazzocchi, Gabriela Sommese, Leandro Matías Palomeque, Julieta Felice, Juan Ignacio Di Carlo, Mariano Nahuel Fainstein, D. González, P. N. Contreras, Paola Skapura, Darlene G. McCauley, Mark D. Lascano, Elena C. Negroni, Jorge A. Kranias, Evangelia G. Wehrens, Xander H. T. Valverde, Carlos Alfredo Mattiazzi, Alicia Ramona |
| author_facet |
Mazzocchi, Gabriela Sommese, Leandro Matías Palomeque, Julieta Felice, Juan Ignacio Di Carlo, Mariano Nahuel Fainstein, D. González, P. N. Contreras, Paola Skapura, Darlene G. McCauley, Mark D. Lascano, Elena C. Negroni, Jorge A. Kranias, Evangelia G. Wehrens, Xander H. T. Valverde, Carlos Alfredo Mattiazzi, Alicia Ramona |
| author_sort |
Mazzocchi, Gabriela |
| title |
Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814 |
| title_short |
Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814 |
| title_full |
Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814 |
| title_fullStr |
Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814 |
| title_full_unstemmed |
Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814 |
| title_sort |
phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with camkii-constitutive phosphorylation of ryr2 at site s2814 |
| publishDate |
2016 |
| url |
http://sedici.unlp.edu.ar/handle/10915/127243 |
| work_keys_str_mv |
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Repositorios |
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1764820451489480706 |