A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate.
A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate.
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DOI：
10.1016/j.hrthm.2020.11.026
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发表时间：
2021-05
期刊：
影响因子：
5.5
通讯作者：
Boyett MR
中科院分区：
文献类型：
--
作者：
D'Souza A;Wang Y;Anderson C;Bucchi A;Baruscotti M;Olieslagers S;Mesirca P;Johnsen AB;Mastitskaya S;Ni H;Zhang Y;Black N;Cox C;Wegner S;Bano-Otalora B;Petit C;Gill E;Logantha SJRJ;Dobrzynski H;Ashton N;Hart G;Zhang R;Zhang H;Cartwright EJ;Wisloff U;Mangoni ME;da Costa Martins PA;Piggins HD;DiFrancesco D;Boyett MR
心率遵循昼夜变化，缓慢的心律主要发生在夜间。睡眠期间较低的心率被认为是神经起源的，但在这里，我们测试了是否涉及内在起搏的昼夜差异。在体内和体外心电图记录，迷走神经切断术，转基因，定量聚合酶链反应，蛋白质印迹，免疫组织化学，膜片钳，报告生物发光记录，染色质免疫沉淀。小鼠平均心率的昼夜差异与平均自发活动的波动无关，并且在药物、手术和转基因中断心脏自主输入的情况下持续存在。离体（即去神经支配）窦房结（SN）制备物的自发搏动率显示出昼夜节律，伴随着离子通道（包括超极化激活的环核苷酸门控钾通道4（HCN 4））的节律性信使RNA表达。体外研究表明，人类HCN 4启动子和相应的有趣电流存在24小时节律。HCN阻断可消除小鼠在体和离体SN的昼夜心率差。在SN和局部时钟的破坏中鉴定了典型昼夜节律时钟转录因子的节律表达，例如，脑和肌肉ARNT样1（BMAL1）和隐花色素（CRY（通过心肌细胞特异性敲除Bmal1）消除了Hcn4和固有心率的昼夜差异。染色质免疫沉淀揭示了Hcn4上的特异性Bmal1结合位点，将本地时钟与固有速率控制相链接。心率的昼夜变化涉及SN局部时钟依赖性Hcn4节律性。数据揭示了一种新的心率调节器和对睡眠期间心动过缓的机械见解。
Heart rate follows a diurnal variation, and slow heart rhythms occur primarily at night. The lower heart rate during sleep is assumed to be neural in origin, but here we tested whether a day-night difference in intrinsic pacemaking is involved. In vivo and in vitro electrocardiographic recordings, vagotomy, transgenics, quantitative polymerase chain reaction, Western blotting, immunohistochemistry, patch clamp, reporter bioluminescence recordings, and chromatin immunoprecipitation were used. The day-night difference in the average heart rate of mice was independent of fluctuations in average locomotor activity and persisted under pharmacological, surgical, and transgenic interruption of autonomic input to the heart. Spontaneous beating rate of isolated (ie, denervated) sinus node (SN) preparations exhibited a day-night rhythm concomitant with rhythmic messenger RNA expression of ion channels including hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4). In vitro studies demonstrated 24-hour rhythms in the human HCN4 promoter and the corresponding funny current. The day-night heart rate difference in mice was abolished by HCN block, both in vivo and in the isolated SN. Rhythmic expression of canonical circadian clock transcription factors, for example, Brain and muscle ARNT-Like 1 (BMAL1) and Cryptochrome (CRY) was identified in the SN and disruption of the local clock (by cardiomyocyte-specific knockout of Bmal1) abolished the day-night difference in Hcn4 and intrinsic heart rate. Chromatin immunoprecipitation revealed specific BMAL1 binding sites on Hcn4, linking the local clock with intrinsic rate control. The circadian variation in heart rate involves SN local clock–dependent Hcn4 rhythmicity. Data reveal a novel regulator of heart rate and mechanistic insight into bradycardia during sleep.
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