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

Aims Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with Ca2+-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 Ca...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Valverde, Carlos Alfredo, Mazzocchi, Gabriela, Di Carlo, Mariano Nahuel, Ciocci Pardo, Alejandro, Salas, Nehuén, Ragone, María Inés, Felice, Juan Ignacio, Cely Ortiz, Diana Catalina Alejandra, Consolini, Alicia Elvira, Portiansky, Enrique Leo, Mosca, Susana María, Kranias, Evangelia G., Wehrens, Xander H. T., Mattiazzi, Alicia Ramona
Formato: Articulo
Lenguaje:Inglés
Publicado: 2018
Materias:
Ciencias Médicas
Arrhythmias
CaMKII
Calcium
Calcium waves
Phospholamban
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/124352
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-124352
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Médicas
Arrhythmias
CaMKII
Calcium
Calcium waves
Phospholamban
spellingShingle Ciencias Médicas
Arrhythmias
CaMKII
Calcium
Calcium waves
Phospholamban
Valverde, Carlos Alfredo
Mazzocchi, Gabriela
Di Carlo, Mariano Nahuel
Ciocci Pardo, Alejandro
Salas, Nehuén
Ragone, María Inés
Felice, Juan Ignacio
Cely Ortiz, Diana Catalina Alejandra
Consolini, Alicia Elvira
Portiansky, Enrique Leo
Mosca, Susana María
Kranias, Evangelia G.
Wehrens, Xander H. T.
Mattiazzi, Alicia Ramona
Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
topic_facet Ciencias Médicas
Arrhythmias
CaMKII
Calcium
Calcium waves
Phospholamban
description Aims Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with Ca2+-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 Ca2+ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation. Methods and results 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 Ca2+ sequestration evoked by PLN ablation in SDKO hearts prevented 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 but rather exacerbated I/R-induced SR Ca2+ leak, as well as mitochondrial alterations, which were greatly avoided by inhibition of RyR2. These results indicate that the increase in SR Ca2+ uptake is ineffective in preventing the enhanced SR Ca2+ leak of PLN ablated myocytes from either entering into nearby mitochondria and/or activating additional CaMKII pathways, contributing to cardiac damage. Conclusion Our results demonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced SR Ca2+ leak. These findings underscore the benefits of increasing SERCA2a activity in the face of SR Ca2+ triggered arrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbates I/R cardiac injury.
format Articulo
Articulo
author Valverde, Carlos Alfredo
Mazzocchi, Gabriela
Di Carlo, Mariano Nahuel
Ciocci Pardo, Alejandro
Salas, Nehuén
Ragone, María Inés
Felice, Juan Ignacio
Cely Ortiz, Diana Catalina Alejandra
Consolini, Alicia Elvira
Portiansky, Enrique Leo
Mosca, Susana María
Kranias, Evangelia G.
Wehrens, Xander H. T.
Mattiazzi, Alicia Ramona
author_facet Valverde, Carlos Alfredo
Mazzocchi, Gabriela
Di Carlo, Mariano Nahuel
Ciocci Pardo, Alejandro
Salas, Nehuén
Ragone, María Inés
Felice, Juan Ignacio
Cely Ortiz, Diana Catalina Alejandra
Consolini, Alicia Elvira
Portiansky, Enrique Leo
Mosca, Susana María
Kranias, Evangelia G.
Wehrens, Xander H. T.
Mattiazzi, Alicia Ramona
author_sort Valverde, Carlos Alfredo
title Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
title_short Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
title_full Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
title_fullStr Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
title_full_unstemmed Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
title_sort ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with ca2+/calmodulin kinase ii constitutive phosphorylation of ryanodine receptors
publishDate 2018
url http://sedici.unlp.edu.ar/handle/10915/124352
work_keys_str_mv AT valverdecarlosalfredo ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT mazzocchigabriela ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT dicarlomarianonahuel ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT cioccipardoalejandro ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT salasnehuen ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT ragonemariaines ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT felicejuanignacio ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT celyortizdianacatalinaalejandra ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT consolinialiciaelvira ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT portianskyenriqueleo ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT moscasusanamaria ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT kraniasevangeliag ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT wehrensxanderht ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
AT mattiazzialiciaramona ablationofphospholambanrescuesreperfusionarrhythmiasbutexacerbatesmyocardiuminfarctioninheartswithca2calmodulinkinaseiiconstitutivephosphorylationofryanodinereceptors
bdutipo_str Repositorios
_version_ 1764820450185052163

Ejemplares similares