Inducible, tissue-specific deletion of Ryr2 in adult mice caused bradycardia, arrhythmia, and hallmarks of heart failure including sudden cardiac death.
Does RYR2 loss-of-function reduce heart rate and rhythmicity in vivo?
In a mouse model, acute loss of cardiac RYR2 protein causes bradycardia, fatal arrhythmias, and heart failure, providing in vivo evidence that RYR2 loss-of-function contributes to disease-associated rhythm disturbances.
AIMS: The molecular mechanisms controlling heart function and rhythmicity are incompletely understood. While it is widely accepted that the type 2 ryanodine receptor (Ryr2) is the major Ca(2+) release channel in excitation-contraction coupling, the role of these channels in setting a consistent beating rate remains controversial. Gain-of-function RYR2 mutations in humans and genetically engineered mouse models are known to cause Ca(2+) leak, arrhythmias, and sudden cardiac death. Embryonic stem-cell derived cardiomyocytes lacking Ryr2 display slower beating rates, but no supporting in vivo evidence has been presented. The aim of the present study was to test the hypothesis that RYR2 loss-of-function would reduce heart rate and rhythmicity in vivo. METHODS AND RESULTS: We generated inducible, tissue-specific Ryr2 knockout mice with acute ∼50% loss of RYR2 protein in the heart but not in other tissues. Echocardiography, working heart perfusion, and in vivo ECG telemetry demonstrated that deletion of Ryr2 was sufficient to cause bradycardia and arrhythmia. Our results also show that cardiac Ryr2 knockout mice exhibit functional and structural hallmarks of heart failure, including sudden cardiac death. CONCLUSION: These results illustrate that the RYR2 channel plays an essential role in pacing heart rate. Moreover, we find that RYR2 loss-of-function can lead to fatal arrhythmias typically associated with gain-of-function mutations. Given that RYR2 levels can be reduced in pathological conditions, including heart failure and diabetic cardiomyopathy, we predict that RYR2 loss contributes to disease-associated bradycardia, arrhythmia, and sudden death.
Bround et al. (Mon,) reported a other. Inducible, tissue-specific Ryr2 knockout was evaluated on Heart rate and rhythmicity. Inducible, tissue-specific deletion of Ryr2 in adult mice caused bradycardia, arrhythmia, and hallmarks of heart failure including sudden cardiac death.
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