Document Detail


Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice.
MedLine Citation:
PMID:  22869620     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-08-06
Journal Detail:
Title:  Cardiovascular research     Volume:  96     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-04-25     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  372-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / genetics,  metabolism*,  physiopathology,  ultrasonography
Biological Clocks*
Bradycardia / genetics,  metabolism,  physiopathology
Cardiac Output
Death, Sudden, Cardiac / etiology
Down-Regulation
Electrocardiography, Ambulatory / methods
Excitation Contraction Coupling
Heart Rate*
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction
Myocardium / metabolism*
RNA, Messenger / metabolism
Ryanodine Receptor Calcium Release Channel / deficiency,  genetics,  metabolism*
Telemetry
Time Factors
Ventricular Function
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/RNA, Messenger; 0/Ryanodine Receptor Calcium Release Channel
Comments/Corrections
Comment In:
Cardiovasc Res. 2012 Dec 1;96(3):343-4   [PMID:  22991333 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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