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Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice.

Abstract：

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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Bround MJ,Asghari P,Wambolt RB,Bohunek L,Smits C,Philit M,Kieffer TJ,Lakatta EG,Boheler KR,Moore ED,Allard MF,Johnson JD

doi

10.1093/cvr/cvs260

subject

Has Abstract

pub_date

2012-12-01 00:00:00

pages

372-80

issue

3

eissn

0008-6363

issn

1755-3245

pii

cvs260

journal_volume

96

pub_type

杂志文章

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