Reversible redox modifications of ryanodine receptor ameliorate ventricular arrhythmias in the ischemic-reperfused heart

Authors
Becerra, Romina Valeria; Roman, Barbara Soledad; Di Carlo, Mariano Nahuel; Mariángelo, Juan Ignacio Elio; Salas, Margarita Ana; Sanchez, Gina; Donoso, Paulina; Schinella, Guillermo Raúl; Vittone, Leticia Beatriz; Wehrens, Xander H.; Mundiña, Cecilia Beatriz; Said, Maria Matilde
Publication Year
2016
Language
English
Format
article
Status
Published version
Description
Previous results from our laboratory showed that phosphorylation of ryanodine receptor 2 (RyR2) by Ca2+ calmodulin-dependent kinase II (CaMKII) was a critical but not the unique event responsible for the production of reperfusion-induced arrhythmogenesis, suggesting the existence of other mechanisms cooperating in an additive way to produce these rhythm alterations. Oxidative stress is a prominent feature of ischemia/reperfusion injury. Both CaMKII and RyR2 are proteins susceptible to alteration by redox modifications. This study was designed to elucidate whether CaMKII and RyR2 redox changes occur during reperfusion and whether these changes are involved in the genesis of arrhythmias. Langendorff-perfused hearts from rats or transgenic mice with genetic ablation of CaMKII phosphorylation site on RyR2 (S2814A) were subjected to ischemia-reperfusion in the presence or absence of a free radical scavenger (mercaptopropionylglycine, MPG) or inhibitors of NADPH oxidase and nitric oxide synthase. Left ventricular contractile parameters and monophasic action potentials were recorded. Oxidation and phosphorylation of CaMKII and RyR2 were assessed. Increased oxidation of CaMKII during reperfusion had no consequences on the level of RyR2 phosphorylation. Avoiding the reperfusion-induced thiol oxidation of RyR2 with MPG produced a reduction in the number of arrhythmias and did not modify the contractile recovery. Conversely, selective prevention of S-nitrosylation and S-glutathionylation of RyR2 was associated with higher numbers of arrhythmias and impaired contractility. In S2814A mice, treatment with MPG further reduced the incidence of arrhythmias. Taken together, the results suggest that redox modification of RyR2 synergistically with CaMKII phosphorylation modulates reperfusion arrhythmias.
Fil: Becerra, Romina Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Roman, Barbara Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Di Carlo, Mariano Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Mariángelo, Juan Ignacio Elio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Salas, Margarita Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Sanchez, Gina. Universidad de Chile; Chile
Fil: Donoso, Paulina. Universidad de Chile; Chile
Fil: Schinella, Guillermo Raúl. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina
Fil: Vittone, Leticia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Wehrens, Xander H.. Baylor College of Medicine; Estados Unidos
Fil: Mundiña, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Said, Maria Matilde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Subject
ARRHYTHMIAS
ISCHEMIA/REPERFUSION
REDOX MODIFICATIONS
RYANODINE RECEPTOR TYPE 2
Inmunología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/54003