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Artículo

Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814

Mazzocchi, GabrielaIcon ; Sommese, Leandro MatíasIcon ; Palomeque, JulietaIcon ; Felice, Juan IgnacioIcon ; Di Carlo, Mariano NahuelIcon ; Fainstein, Diego GermánIcon ; Gonzalez, P.; Contreras, P.; Skapura, D.; Mccauley, M. D.; Lascano, E. C.; Negroni, Jorge Antonio; Kranias, E. G.; Wehrens, X. H. T.; Valverde, Carlos AlfredoIcon ; Mattiazzi, Ramona AliciaIcon
Fecha de publicación: 06/2016
Editorial: Wiley Blackwell Publishing, Inc
Revista: The Journal Of Physiology
ISSN: 0022-3751
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Biológicas

Resumen

Mice with constitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D+/+) 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+/+ mice. We generated phospholamban (PLN)-deficient/S2814D+/+ knock-in mice by crossing two colonies, S2814D+/+ and PLNKO mice (SD+/+/KO). SD+/+/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+/+ myocytes. Ventricular arrhythmias evoked by catecholaminergic challenge (caffeine/adrenaline) in S2814D+/+ mice in vivo or programmed electric stimulation and high extracellular Ca2+ in S2814D+/- hearts ex vivo 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+/+ mice into non-propagated Ca2+ mini-waves on confocal microscopy. Myocyte Ca2+ waves, typical of S2814D+/+ mice, could be evoked in SD+/+/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.
Palabras clave: S2814d Mice , Sdko Mice , Arrhythmia , Myocyte Model
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/51492
DOI: https://dx.doi.org/10.1113/JP271622
URL: https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP271622
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Articulos(CIC)
Articulos de CENTRO DE INVEST.CARDIOVASCULARES (I)
Citación
Mazzocchi, Gabriela; Sommese, Leandro Matías; Palomeque, Julieta; Felice, Juan Ignacio; Di Carlo, Mariano Nahuel; et al.; Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814; Wiley Blackwell Publishing, Inc; The Journal Of Physiology; 594; 11; 6-2016; 3005-3030
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