CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
DI CARLO, MARIANO N; RAGONE, MARÍA INES; CONSOLINI, ALICIA E; KRANIAS, EVANGELIA G; VALVERDE, CARLOS A; CIOCCI PARDO, ALEJANDRO; FELICE, JUAN I; PORTIANSKY, ENRIQUE; WEHRENS, XANDER H T; VALVERDE, CARLOS A; CIOCCI PARDO, ALEJANDRO; FELICE, JUAN I; PORTIANSKY, ENRIQUE; WEHRENS, XANDER H T; MAZZOCCHI, GABRIELA; SALAS, NEHUEN; CELY-ORTIZ, ALEJANDRA; MOSCA, SUSANA; MATTIAZZI, ALICIA; MAZZOCCHI, GABRIELA; SALAS, NEHUEN; CELY-ORTIZ, ALEJANDRA; MOSCA, SUSANA; MATTIAZZI, ALICIA; DI CARLO, MARIANO N; RAGONE, MARÍA INES; CONSOLINI, ALICIA E; KRANIAS, EVANGELIA G
OXFORD UNIV PRESS
Lugar: Oxford; Año: 2019 vol. 115 p. 556 - 569
Abnormal Ca2þ release from the sarcoplasmic reticulum (SR), associated with Ca2þ-calmodulin kinase II (CaMKII)-dependent phosphorylation of RyR2 at Ser2814, has consistently been linked to arrhythmogenesis and ischaemia/reperfusion (I/R)-induced cell death. In contrast, the role played by SR Ca2þ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2þ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation.We used WT mice, which have been previously shown to exhibit a transient increase in RyR2-Ser2814 phosphorylation at the onset of reperfusion; mice with constitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbate CaMKII-dependent reperfusion arrhythmias and cardiac damage, and phospholamban (PLN)-deficient- S2814D knock-in (SDKO) mice resulting from crossbreeding S2814D with phospholamban knockout deficient (PLNKO) mice. At baseline, S2814D and SDKO mice had structurally normal hearts. Moreover none of the strains were arrhythmic before ischaemia. Upon cardiac I/R, WT, and S2814D hearts exhibited abundant arrhythmias that were prevented by PLN ablation. In contrast, PLN ablation increased infarct size compared with WT and S2814D hearts. Mechanistically, the enhanced SR Ca2þ sequestration evoked by PLN ablation in SDKO hearts prevented arrhythmogenic events upon reperfusion by fragmenting SR Ca2þ waves into non-propagated and nonarrhythmogenic events (mini-waves). Conversely, the increase in SR Ca2þ sequestration did not reduce but rather exacerbated I/R-induced SR Ca2þ leak, as well as mitochondrial alterations, which were greatly avoided by inhibition of RyR2. These results indicate that the increase in SR Ca2þ uptake is ineffective in preventing the enhanced SR Ca2þ leak of PLN ablated myocytes from either entering into nearby mitochondria and/or activating additional CaMKII pathways, contributing to cardiac damage.Our results demonstrate that increasing SR Ca2þ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced SR Ca2þ leak. These findings underscore the benefits of increasing SERCA2a activity in the face of SR Ca2þ triggered arrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbates I/R cardiac injury.