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Ca2+-CaM dependent inactivation of RyR2 underlies Ca2+ alternans in intact heart
dc.contributor.author | Guo, Wenting |
dc.contributor.author | Benítez Iglesias, Raúl |
dc.contributor.author | Hove-Madsen, Leif |
dc.contributor.author | Álvarez Lacalle, Enrique |
dc.contributor.author | Echebarría Domínguez, Blas |
dc.contributor.other | Universitat Politècnica de Catalunya. Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial |
dc.contributor.other | Universitat Politècnica de Catalunya. Departament de Física |
dc.date.accessioned | 2021-06-03T12:48:39Z |
dc.date.available | 2021-06-03T12:48:39Z |
dc.date.issued | 2021-02-19 |
dc.identifier.citation | Guo, W. [et al.]. Ca2+-CaM dependent inactivation of RyR2 underlies Ca2+ alternans in intact heart. "Circulation research", 19 Febrer 2021, vol. 128, núm. 4, p. e63-e83. |
dc.identifier.issn | 0009-7330 |
dc.identifier.uri | http://hdl.handle.net/2117/346596 |
dc.description.abstract | Rationale: Ca2+ alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca2+ alternans remains undefined. Increasing evidence suggests that Ca2+ alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca2+ alternans are unknown. Objective: To determine the role of CaM (calmodulin) on Ca2+ alternans in intact working mouse hearts. Methods and Results: We used an in vivo local gene delivery approach to alter CaM function by directly injecting adenoviruses expressing CaM-wild type, a loss-of-function CaM mutation, CaM (1–4), and a gain-of-function mutation, CaM-M37Q, into the anterior wall of the left ventricle of RyR2 wild type or mutant mouse hearts. We monitored Ca2+ transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca2+ imaging. We found that CaM-wild type and CaM-M37Q promoted Ca2+ alternans and prolonged Ca2+ transient recovery in intact RyR2 wild type and mutant hearts, whereas CaM (1–4) exerted opposite effects. Altered CaM function also affected the recovery from inactivation of the L-type Ca2+ current but had no significant impact on sarcoplasmic reticulum Ca2+ content. Furthermore, we developed a novel numerical myocyte model of Ca2+ alternans that incorporates Ca2+-CaM-dependent regulation of RyR2 and the L-type Ca2+ channel. Remarkably, the new model recapitulates the impact on Ca2+ alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca2+ elevation as a result of rapid pacing triggers Ca2+-CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca2+ release, which, in turn, reduces diastolic cytosolic Ca2+, leading to alternations in diastolic cytosolic Ca2+, RyR2 inactivation, and sarcoplasmic reticulum Ca2+ release (ie, Ca2+ alternans). Conclusions: Our results demonstrate that inactivation of RyR2 by Ca2+-CaM is a major determinant of Ca2+ alternans, making Ca2+-CaM dependent regulation of RyR2 an important therapeutic target for cardiac alternans. |
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::Electrònica biomèdica::Electrònica en cardiologia |
dc.title | Ca2+-CaM dependent inactivation of RyR2 underlies Ca2+ alternans in intact heart |
dc.type | Article |
dc.subject.lemac | Electrònica en cardiologia |
dc.contributor.group | Universitat Politècnica de Catalunya. ANCORA - Anàlisi i control del ritme cardíac |
dc.contributor.group | Universitat Politècnica de Catalunya. BIOCOM-SC - Grup de Biologia Computacional i Sistemes Complexos |
dc.identifier.doi | 10.1161/CIRCRESAHA.120.318429 |
dc.description.peerreviewed | Peer Reviewed |
dc.relation.publisherversion | https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.318429 |
dc.rights.access | Open Access |
local.identifier.drac | 30614188 |
dc.description.version | Postprint (author's final draft) |
local.citation.author | Guo, W.; Benitez, R.; Hove-Madsen, L.; Alvarez-Lacalle, E.; Echebarria, B. |
local.citation.publicationName | Circulation research |
local.citation.volume | 128 |
local.citation.number | 4 |
local.citation.startingPage | e63 |
local.citation.endingPage | e83 |
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