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Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2
Francisco J. Alvarado, … , Michael J. Ackerman, Héctor H. Valdivia
Francisco J. Alvarado, … , Michael J. Ackerman, Héctor H. Valdivia
Published March 5, 2019
Citation Information: JCI Insight. 2019;4(7):e126544. https://doi.org/10.1172/jci.insight.126544.
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Research Article Cardiology

Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2

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Abstract

Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a potentially novel mutation in ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain of function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 year of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 months of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally divergent behavior triggers arrhythmias and structural cardiac remodeling, and it involves overexpression of CaM as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.

Authors

Francisco J. Alvarado, J. Martijn Bos, Zhiguang Yuchi, Carmen R. Valdivia, Jonathan J. Hernández, Yan-Ting Zhao, Dawn S. Henderlong, Yan Chen, Talia R. Booher, Cherisse A. Marcou, Filip Van Petegem, Michael J. Ackerman, Héctor H. Valdivia

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Figure 7

Susceptibility to spontaneous Ca2+ release in ventricular myocytes from 1-year-old mice.

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Susceptibility to spontaneous Ca2+ release in ventricular myocytes from ...
(A) Representative traces of WT and Homo ventricular myocytes stimulated with 300 nM isoproterenol (Iso), paced at 3 Hz for 30 seconds, and monitored at rest for 30 seconds. Enzymatically isolated cardiac myocytes were loaded with the fluorescent Ca2+ indicator fluo-4 AM and field stimulated as indicated. Line-scan images were recorded using a confocal microscope. (B) Percentage of cells showing spontaneous Ca2+ release events (SCR, defined as Ca2+ waves) during the monitoring period. SCR incidence is increased in Homo mice in basal conditions (n = 3 hearts per genotype. *P < 0.05, 1-way ANOVA). (C) Average number of SCR events in 30 seconds of monitoring after a 3 Hz train of stimulation (left, individual measurements from n = 17 WT, 16 Het, 16 Homo basal cells and 12 WT, 14 Het, 23 Homo iso-stimulated cells; right, mean values for n = 3 hearts per genotype. *P < 0.05, 1-way ANOVA).

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