Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice
Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice
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DOI：
10.1093/cvr/cvs260
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发表时间：
2012-12-01
影响因子：
10.8
通讯作者：
Johnson, James D.
中科院分区：
文献类型：
--
作者：
Bround, Michael J.;Asghari, Parisa;Johnson, James D.
控制心脏功能和节律性的分子机制尚不完全清楚。虽然人们普遍认为 2 型兰尼碱受体 (Ryr2) 是兴奋收缩耦合中主要的 Ca-2 释放通道，但这些通道在设定一致的搏动速率中的作用仍然存在争议。已知人类和基因工程小鼠模型中的功能获得性 RYR2 突变会导致 Ca-2 渗漏、心律失常和心源性猝死。缺乏 Ryr2 的胚胎干细胞衍生的心肌细胞显示出较慢的搏动速率，但尚未提供支持的体内证据。本研究的目的是检验 RYR2 功能丧失会降低体内心率和节律性的假设。我们生成了可诱导的、组织特异性的 Ryr2 敲除小鼠，其心脏中的 RYR2 蛋白急性缺失约 50%，但其他组织中没有。超声心动图、工作心脏灌注和体内心电图遥测表明，Ryr2 的缺失足以引起心动过缓和心律失常。我们的结果还表明，心脏 Ryr2 基因敲除小鼠表现出心力衰竭的功能和结构特征，包括心源性猝死。这些结果说明 RYR2 通道在心率起搏中发挥重要作用。此外，我们发现 RYR2 功能丧失可导致致命性心律失常，通常与功能获得突变相关。鉴于 RYR2 水平在病理条件下（包括心力衰竭和糖尿病心肌病）会降低，我们预测 RYR2 缺失会导致疾病相关的心动过缓、心律失常和猝死。
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 excitationcontraction 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.We generated inducible, tissue-specific Ryr2 knockout mice with acute approximate to 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.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.