Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice

Michael J. Bround, Parisa Asghari, Rich B. Wambolt, Lubos Bohunek, Claire Smits, Marjolaine Philit, Timothy J. Kieffer, Edward G. Lakatta, Kenneth R. Boheler, Edwin D.W. Moore, Michael F. Allard, James D. Johnson

Research output: Contribution to journalArticlepeer-review

Abstract

AimsThe 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 Ca2+ 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 resultsWe 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.ConclusionThese 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.

Original languageEnglish (US)
Pages (from-to)372-380
Number of pages9
JournalCardiovascular research
Volume96
Issue number3
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

Keywords

  • Arrhythmia (mechanisms)
  • Bradycardia
  • Ca channel
  • Excitation-contraction coupling
  • Heart rate (variability)

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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