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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 8

Susceptibility to ventricular arrhythmia in P1124L mice challenged with epinephrine/caffeine at 8 months of age.

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Susceptibility to ventricular arrhythmia in P1124L mice challenged with ...
(A) Two-second representative lead-II ECG traces from mice undergoing arrhythmia challenge. Mice were anesthetized using isoflurane, and the basal ECG was monitored for 10–15 minutes. The ECG was further monitored for 30 minutes, following an i.p. injection of epinephrine (2 mg/kg) and caffeine (120 mg/kg) (Epi/Caff). From top to bottom, the traces indicate sinus rhythm; premature ventricular beats; nonsustained ventricular bigeminy; and bidirectional ventricular tachycardia (BDVT). (B–D) Average number of premature ventricular beats and episodes of nonsustained (lasting ≤5 seconds) and sustained arrhythmias (lasting >5 seconds) in mice undergoing arrhythmia challenge. (E) Incidence of sustained BDVT, defined as ectopic beats with alternating axes of depolarization (n = 7 mice per genotype. *P < 0.05 vs. WT, ANOVA on ranks [B–C], 1-way ANOVA [D], z test [E]).

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