CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
artículos
Título:
Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2.
Autor/es:
MAZZOCCHI, GABRIELA; FELICE, JUAN IGNACIO; LASCANO EL; MATTIAZZI, ALICIA; SOMMESE, LEANDRO; DI CARLO, MARIANO; NEGRONI JA; PALOMEQUE, JULIETA; FAINSTEIN, DIEGO; VALVERDE, CARLOS
Revista:
THE JOURNAL OF PHYSIOLOGY
Editorial:
WILEY-BLACKWELL PUBLISHING, INC
Referencias:
Lugar: Londres; Año: 2016 vol. 594 p. 3005 - 3030
ISSN:
0022-3751
Resumen:
Mice with constitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D+/+) haveincreased propensity to arrhythmias under β-adrenergic stress conditions. Although abnormalCa2+ release from the sarcoplasmic reticulum (SR) has been linked to arrhythmogenesis,the role played by SR Ca2+ uptake remains controversial. We tested the hypothesis thatan increase in SR Ca2+ uptake is able to rescue the increased arrhythmia propensity ofS2814D+/+ mice. We generated phospholamban (PLN)-deficient/S2814D+/+ knock-in mice bycrossing two colonies, S2814D+/+ and PLNKO mice (SD+/+/KO). SD+/+/KO myocytes exhibitedboth increased SR Ca2+ uptake seen in PLN knock-out (PLNKO) myocytes and diminishedSR Ca2+ load (relative to PLNKO), a characteristic of S2814D+/+ myocytes. Ventriculararrhythmias evoked by catecholaminergic challenge (caffeine/adrenaline) in S2814D+/+ micein vivo or programmed electric stimulation and high extracellular Ca2+ in S2814D+/− heartsex vivo were significantly diminished by PLN ablation. At the myocyte level, PLN ablationconverted the arrhythmogenic Ca2+ waves evoked by high extracellular Ca2+ provocation inS2814D+/+ 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 inhibitingSERCA2a. A mathematical human myocyte model replicated these results and allowed forpredicting the increase in SR Ca2+ uptake required to prevent the arrhythmias induced bya Ca2+?calmodulin-dependent protein kinase (CaMKII)-dependent leaky RyR2. Our resultsdemonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic eventstriggered by SR Ca2+ leak due to CaMKII-dependent phosphorylation of the RyR2-S2814 siteand underscore the benefits of increasing SERCA2a activity on SR Ca2+-triggered arrhythmias.