The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2+-ATPase, is a major determinant of Ca2+ alternans in intact mouse hearts.
J Biol Chem
; 293(35): 13650-13661, 2018 08 31.
Article
em En
| MEDLINE
| ID: mdl-29986885
ABSTRACT
Sarcoplasmic reticulum (SR) Ca2+ cycling is governed by the cardiac ryanodine receptor (RyR2) and SR Ca2+-ATPase (SERCA2a). Abnormal SR Ca2+ cycling is thought to be the primary cause of Ca2+ alternans that can elicit ventricular arrhythmias and sudden cardiac arrest. Although alterations in either RyR2 or SERCA2a function are expected to affect SR Ca2+ cycling, whether and to what extent altered RyR2 or SERCA2a function affects Ca2+ alternans is unclear. Here, we employed a gain-of-function RyR2 variant (R4496C) and the phospholamban-knockout (PLB-KO) mouse model to assess the effect of genetically enhanced RyR2 or SERCA2a function on Ca2+ alternans. Confocal Ca2+ imaging revealed that RyR2-R4496C shortened SR Ca2+ release refractoriness and markedly suppressed rapid pacing-induced Ca2+ alternans. Interestingly, despite enhancing RyR2 function, intact RyR2-R4496C hearts exhibited no detectable spontaneous SR Ca2+ release events during pacing. Unlike for RyR2, enhancing SERCA2a function by ablating PLB exerted a relatively minor effect on Ca2+ alternans in intact hearts expressing RyR2 WT or a loss-of-function RyR2 variant, E4872Q, that promotes Ca2+ alternans. Furthermore, partial SERCA2a inhibition with 3 µm 2,5-di-tert-butylhydroquinone (tBHQ) also had little impact on Ca2+ alternans, whereas strong SERCA2a inhibition with 10 µm tBHQ markedly reduced the amplitude of Ca2+ transients and suppressed Ca2+ alternans in intact hearts. Our results demonstrate that enhanced RyR2 function suppresses Ca2+ alternans in the absence of spontaneous Ca2+ release and that RyR2, but not SERCA2a, is a key determinant of Ca2+ alternans in intact working hearts, making RyR2 an important therapeutic target for cardiac alternans.
Palavras-chave
Ca2+ alternans; Ca2+ release refractoriness; calcium; calcium ATPase; calcium imaging; calcium intracellular release; cardiac dysfunction; confocal Ca2+ imaging; endoplasmic reticulum (ER); intact heart imaging; phospholamban; ryanodine receptor; sarcoplasmic reticulum (SR); ventricular tachyarrhythmia
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cálcio
/
Canal de Liberação de Cálcio do Receptor de Rianodina
/
ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático
/
Miocárdio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article