Artículos de revistas
Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814
Fecha
2016-06Registro en:
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
0022-3751
CONICET Digital
CONICET
Autor
Mazzocchi, Gabriela
Sommese, Leandro Matías
Palomeque, Julieta
Felice, Juan Ignacio
Di Carlo, Mariano Nahuel
Fainstein, Diego Germán
Gonzalez, P.
Contreras, P.
Skapura, D.
Mccauley, M. D.
Lascano, E. C.
Negroni, Jorge Antonio
Kranias, E. G.
Wehrens, X. H. T.
Valverde, Carlos Alfredo
Mattiazzi, Ramona Alicia
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.