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Ca2+-CaM Dependent Inactivation of RyR2 Underlies Ca2+ Alternans in Intact Heart.
Wei, Jinhong; Yao, Jinjing; Belke, Darrell; Guo, Wenting; Zhong, Xiaowei; Sun, Bo; Wang, Ruiwu; Paul Estillore, John; Vallmitjana, Alexander; Benitez, Raul; Hove-Madsen, Leif; Alvarez-Lacalle, Enrique; Echebarria, Blas; Chen, S R Wayne.
Afiliação
  • Wei J; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Yao J; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Belke D; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Guo W; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Zhong X; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Sun B; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Wang R; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Paul Estillore J; Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta, Canada (J.W., J.Y., D.B., W.G., X.Z., B.S., R.W., J.P.E., S.R.W.C.).
  • Vallmitjana A; Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain (A.V., R.B.).
  • Benitez R; Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain (A.V., R.B.).
  • Hove-Madsen L; Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain (R.B.).
  • Alvarez-Lacalle E; Biomedical Research Institute Barcelona IIBB-CSIC, CIBERCV and IIB Sant Pau, Hospital de Sant Pau, Barcelona, Spain (L.H.-M.).
  • Echebarria B; Department of Physics, Universitat Politècnica de Catalunya, Barcelona, Spain (E.A.-L., B.E.).
  • Chen SRW; Department of Physics, Universitat Politècnica de Catalunya, Barcelona, Spain (E.A.-L., B.E.).
Circ Res ; 128(4): e63-e83, 2021 02 19.
Article em En | MEDLINE | ID: mdl-33375811
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canal de Liberação de Cálcio do Receptor de Rianodina / Sinalização do Cálcio / Miócitos Cardíacos / Coração Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Circ Res Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canal de Liberação de Cálcio do Receptor de Rianodina / Sinalização do Cálcio / Miócitos Cardíacos / Coração Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Circ Res Ano de publicação: 2021 Tipo de documento: Article