Ca(2+)-CaM Dependent Inactivation of RyR2 Underlies Ca(2+) Alternans in Intact Heart.
Por:
Wei J, Yao J, Belke D, Guo W, Zhong X, Sun B, Wang R, Paul Estillore J, Vallmitjana A, Benítez R, Hove-Madsen L, Alvarez-Lacalle E, Echebarria B and Chen SRW
Publicada:
19 feb 2021
Ahead of Print:
30 dic 2020
Categoría:
Cardiology and cardiovascular medicine
Resumen:
RATIONALE: Ca(2+) alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca(2+) alternans remains undefined. Increasing evidence suggests that Ca(2+) alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca(2+) alternans are unknown. OBJECTIVE: To determine the role of CaM (calmodulin) on Ca(2+) 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 Ca(2+) transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca(2+) imaging. We found that CaM-wild type and CaM-M37Q promoted Ca(2+) alternans and prolonged Ca(2+) 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 Ca(2+) current but had no significant impact on sarcoplasmic reticulum Ca(2+) content. Furthermore, we developed a novel numerical myocyte model of Ca(2+) alternans that incorporates Ca(2+)-CaM-dependent regulation of RyR2 and the L-type Ca(2+) channel. Remarkably, the new model recapitulates the impact on Ca(2+) alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca(2+) elevation as a result of rapid pacing triggers Ca(2+)-CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca(2+) release, which, in turn, reduces diastolic cytosolic Ca(2+), leading to alternations in diastolic cytosolic Ca(2+), RyR2 inactivation, and sarcoplasmic reticulum Ca(2+) release (ie, Ca(2+) alternans). CONCLUSIONS: Our results demonstrate that inactivation of RyR2 by Ca(2+)-CaM is a major determinant of Ca(2+) alternans, making Ca(2+)-CaM dependent regulation of RyR2 an important therapeutic target for cardiac alternans.
Filiaciones:
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.)
Benítez R:
Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain (A.V., R.B.)
Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain (R.B.)
Hove-Madsen L:
Biomedical Research Institute Barcelona IIBB-CSIC, CIBERCV and IIB Sant Pau, Hospital de Sant Pau, Barcelona, Spain (L.H.-M.)
Alvarez-Lacalle E:
Department of Physics, Universitat Politècnica de Catalunya, Barcelona, Spain (E.A.-L., B.E.)
Echebarria B:
Department of Physics, Universitat Politècnica de Catalunya, Barcelona, Spain (E.A.-L., B.E.)
Chen SRW:
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.)
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