Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors

VALVERDE, CARLOS ALFREDO; MAZZOCCHI, GABRIELA; DI CARLO, MARIANO NAHUEL; CIOCCI-PARDO, ALEJANDRO; SALAS, NEHUÉN; RAGONE, MARÍA INES; FELICE, JUAN IGNACIO; CELY-ORTIZ, DIANA CATALINA ALEJANDRA; CONSOLINI, ALICIA ELVIRA; PORTIANSKY, ENRIQUE LEO; MOSCA, SUSANA ; KRANIAS, EVANGELINA GALANI; WEHRENS, XANDER H T; MATTIAZZI, RAMONA ALICIA

CARDIOVASCULAR RESEARCH

OXFORD UNIV PRESS

Lugar: Oxford; Año: 2018

0008-6363

AimsAbnormal Ca2+release from the sarcoplasmic reticulum (SR), associated with Ca2+-calmodulinkinase II (CaMKII)-dependent phosphorylation of RyR2 at Ser2814, hasconsistently been linked to arrhythmogenesis and ischaemia/reperfusion (I/R)-inducedcell death. In contrast, the role played by SR Ca2+ uptake underthese stress conditions remains controversial. We tested the hypothesis that anincrease in SR Ca2+ uptake is able to attenuate reperfusionarrhythmias and cardiac injury elicited by increased RyR2-Ser2814phosphorylation.Methods and resultsWe used WT mice,which have been previously shown to exhibit a transient increase inRyR2-Ser2814 phosphorylation at the onset of reperfusion; mice withconstitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbateCaMKII-dependent reperfusion arrhythmias and cardiac damage, and phospholamban(PLN)-deficient-S2814D knock-in (SDKO) mice resulting from crossbreeding S2814Dwith phospholamban knockout deficient (PLNKO) mice. At baseline, S2814D andSDKO mice had structurally normal hearts. Moreover none of the strains werearrhythmic before ischaemia. Upon cardiac I/R, WT, and S2814D hearts exhibitedabundant arrhythmias that were prevented by PLN ablation. In contrast, PLN ablationincreased infarct size compared with WT and S2814D hearts. Mechanistically, theenhanced SR Ca2+ sequestration evoked by PLN ablation in SDKO heartsprevented arrhythmogenic events upon reperfusion by fragmenting SR Ca2+waves into non-propagated and non-arrhythmogenic events (mini-waves).Conversely, the increase in SR Ca2+ sequestration did not reduce butrather exacerbated I/R-induced SR Ca2+ leak, as well asmitochondrial alterations, which were greatly avoided by inhibition of RyR2.These results indicate that the increase in SR Ca2+ uptake isineffective in preventing the enhanced SR Ca2+ leak of PLN ablatedmyocytes from either entering into nearby mitochondria and/or activatingadditional CaMKII pathways, contributing to cardiac damage.ConclusionOur resultsdemonstrate that increasing SR Ca2+ uptake by PLN ablation canprevent the arrhythmic events triggered by CaMKII-dependent phosphorylation ofRyR2-induced SR Ca2+ leak. These findings underscore the benefits ofincreasing SERCA2a activity in the face of SR Ca2+ triggeredarrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbatesI/R cardiac injury.