Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
Background: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/–, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has...
| Autores: | , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universitat Politècnica de Catalunya (UPC) |
| Repositorio: | UPCommons. Portal del coneixement obert de la UPC |
| Idioma: | inglés |
| OAI Identifier: | oai:upcommons.upc.edu:2117/398769 |
| Acceso en línea: | https://hdl.handle.net/2117/398769 https://dx.doi.org/10.1161/CIRCRESAHA.123.322504 |
| Access Level: | acceso abierto |
| Palabra clave: | Electronics in cardiology Electrònica en cardiologia Àrees temàtiques de la UPC::Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologia |
| Sumario: | Background: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/–, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/– loss-of-function mutation on cardiac structure and function. Methods: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/– mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/– mutation. Results: As in humans, RyR2-I4855M+/– mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/– mice were highly susceptible to electrical stimulation–induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/– mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/– mutation abolished sarcoplasmic reticulum store overload–induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/– mutant compared with wild type. Conclusions: The RyR2-I4855M+/– mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/– mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC. |
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