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dc.contributor.authorSun, Bo
dc.contributor.authorWei, Jinhong
dc.contributor.authorZhong, Xiaowei
dc.contributor.authorVallmitjana Lees, Alexander
dc.contributor.authorBenítez Iglesias, Raúl
dc.contributor.otherUniversitat Politècnica de Catalunya. Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial
dc.identifier.citationSun, B., Wei, J., Zhong, X., Vallmitjana, A., Benitez, R. The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts. "The journal of biological chemistry (Versió web)", 9 Juliol 2018, vol. 293, p. 13650-13677.
dc.description.abstractSarcoplasmic 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 wildtype 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, while 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.
dc.format.extent28 p.
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Spain
dc.subjectÀrees temàtiques de la UPC::Enginyeria biomèdica
dc.subject.lcshVentricular tachycardia
dc.subject.lcshEndoplasmic reticulum
dc.subject.otherVentricular tachyarrhythmia
dc.subject.otherCa2+ alternans
dc.subject.otherCa2+ release refractoriness
dc.subject.otherintact heart imaging
dc.subject.othercalcium intracellular release
dc.subject.othercalcium ATPase
dc.subject.otherryanodine receptor
dc.subject.othersarcoplasmic reticulum (SR)
dc.subject.othercalcium imaging
dc.subject.otherendoplasmic reticulum (ER)
dc.titleThe cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
dc.subject.lemacTaquicàrdia ventricular
dc.contributor.groupUniversitat Politècnica de Catalunya. B2SLab - Bioinformatics and Biomedical Signals Laboratory
dc.contributor.groupUniversitat Politècnica de Catalunya. ANCORA - Anàlisi i control del ritme cardíac
dc.description.peerreviewedPeer Reviewed
dc.rights.accessOpen Access
dc.description.versionPostprint (published version)
local.citation.authorSun, B.; Wei, J.; Zhong, X.; Vallmitjana, A.; Benitez, R.
local.citation.publicationNameThe journal of biological chemistry (Versió web)

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