The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
dc.contributor.author | Sun, Bo |
dc.contributor.author | Wei, Jinhong |
dc.contributor.author | Zhong, Xiaowei |
dc.contributor.author | Vallmitjana Lees, Alexander |
dc.contributor.author | Benítez Iglesias, Raúl |
dc.contributor.other | Universitat Politècnica de Catalunya. Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial |
dc.date.accessioned | 2018-11-30T09:29:21Z |
dc.date.available | 2019-07-09T00:25:33Z |
dc.date.issued | 2018-07-09 |
dc.identifier.citation | Sun, 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.identifier.issn | 1083-351X |
dc.identifier.uri | http://hdl.handle.net/2117/125271 |
dc.description.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 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.extent | 28 p. |
dc.language.iso | eng |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 Spain |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ |
dc.subject | Àrees temàtiques de la UPC::Enginyeria biomèdica |
dc.subject.lcsh | Ventricular tachycardia |
dc.subject.lcsh | Calcium |
dc.subject.lcsh | Ryanodine--Receptors |
dc.subject.lcsh | Endoplasmic reticulum |
dc.subject.other | Ventricular tachyarrhythmia |
dc.subject.other | Ca2+ alternans |
dc.subject.other | Ca2+ release refractoriness |
dc.subject.other | phospholamban |
dc.subject.other | intact heart imaging |
dc.subject.other | calcium intracellular release |
dc.subject.other | calcium |
dc.subject.other | calcium ATPase |
dc.subject.other | ryanodine receptor |
dc.subject.other | sarcoplasmic reticulum (SR) |
dc.subject.other | calcium imaging |
dc.subject.other | endoplasmic reticulum (ER) |
dc.title | The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts |
dc.type | Article |
dc.subject.lemac | Calci |
dc.subject.lemac | Taquicàrdia ventricular |
dc.contributor.group | Universitat Politècnica de Catalunya. B2SLab - Bioinformatics and Biomedical Signals Laboratory |
dc.contributor.group | Universitat Politècnica de Catalunya. ANCORA - Anàlisi i control del ritme cardíac |
dc.identifier.doi | 10.1074/jbc.RA118.003760 |
dc.description.peerreviewed | Peer Reviewed |
dc.relation.publisherversion | http://www.jbc.org/content/early/2018/07/09/jbc.RA118.003760.abstract |
dc.rights.access | Open Access |
local.identifier.drac | 23340926 |
dc.description.version | Postprint (published version) |
local.citation.author | Sun, B.; Wei, J.; Zhong, X.; Vallmitjana, A.; Benitez, R. |
local.citation.publicationName | The journal of biological chemistry (Versió web) |
local.citation.volume | 293 |
local.citation.startingPage | 13650 |
local.citation.endingPage | 13677 |
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