A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate

被引：50

作者：

D'Souza, Alicia ^{[1
]}

Wang, Yanwen ^{[1
]}

Anderson, Cali ^{[1
]}

Bucchi, Annalisa ^{[2
]}

Baruscotti, Mirko ^{[2
]}

Olieslagers, Serve ^{[3
]}

Mesirca, Pietro ^{[4
]}

Johnsen, Anne Berit ^{[5
]}

Mastitskaya, Svetlana ^{[6
]}

Ni, Haibo ^{[1
]}

Zhang, Yu ^{[1
]}

Black, Nicholas ^{[1
]}

Cox, Charlotte ^{[1
]}

Wegner, Sven ^{[1
]}

Bano-Otalora, Beatriz ^{[1
]}

Petit, Cheryl ^{[1
]}

Gill, Eleanor ^{[1
]}

Logantha, Sunil Jit R. J. ^{[1
,8
]}

Dobrzynski, Halina ^{[1
]}

Ashton, Nick ^{[1
]}

Hart, George

Zhang, Rai ^{[7
]}

Zhang, Henggui ^{[1
]}

Cartwright, Elizabeth J. ^{[1
]}

Wisloff, Ulrik

Mangoni, Matteo E.

Da Costa Martins, Paula A. ^{[3
]}

Piggins, Hugh D. ^{[11
]}

DiFrancesco, Dario ^{[2
,10
]}

Boyett, Mark R. ^{[9
]}

机构：

[1] Univ Manchester, Div Cardiovasc Sci, 46 Grafton St, Manchester M13 9NT, Lancs, England

[2] Univ Milan, Dept Biosci, Milan, Italy

[3] Maastricht Univ, Dept Cardiol, Maastricht, Netherlands

[4] Univ Montpellie, CNRS, Inst Genom Fonctionnelle, Montpellier, France

[5] Norwegian Univ Sci & Technol, Dept Circulat & Med Imaging, Trondheim, Norway

[6] UCL, Neurosci Physiol & Pharmacol, London, England

[7] Univ Bristol, Sch Civil Aerosp & Mech Engn, Bristol, Avon, England

[8] Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, Copenhagen, Denmark

[9] Univ Liverpool, Liverpool Ctr Cardiovasc Sci, Liverpool, Merseyside, England

[10] IBF CNR, Milan, Italy

[11] Univ Bristol, Sch Physiol Pharmacol Neurosci, Bristol, Avon, England

来源：

HEART RHYTHM | 2021年 / 18卷 / 05期

基金：

英国生物技术与生命科学研究理事会;

关键词：

Bradycardia; Circadian rhythm; Pacemaking; Sinus node; Vagus nerve; AUTONOMIC CONTROL; RATE-VARIABILITY; BLOOD-PRESSURE; PACEMAKER; TRANSCRIPTION; BAROREFLEX; CHANNEL; DISEASE; BINDING; CRY2;

D O I：

10.1016/j.hrthm.2020.11.026

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Heart rate follows a diurnal variation, and slow heart rhythms occur primarily at night. OBJECTIVE 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. METHODS In vivo and in vitro electrocardiographic recordings, vagotomy, transgenics, quantitative polymerase chain reaction, Western blotting, immunohistochemistry, patch damp, reporter bioluminescence recordings, and chromatin immunoprecipitation were used. RESULTS 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 dock transcription factors, for example, Brain and muscle ARNT-Like 1 (BMAL1) and Cryptochrome (CRY) was identified in the SN and disruption of the local dock (by cardiomyocyte-specific knockout of Bmall) abolished the day-night difference in Hcn4 and intrinsic heart rate. Chromatin immunoprecipitation revealed specific BMAL1 binding sites on Hcn4, linking the local dock with intrinsic rate control. CONCLUSION The circadian variation in heart rate involves SN local dock-dependent Hcn4 rhythmicity. Data reveal a novel regulator of heart rate and mechanistic insight into bradycardia during sleep.

引用

页码：801 / 810

页数：10

共 26 条

[11] RETRACTED: Measuring Circadian and Acute Light Responses in Mice using Wheel Running Activity (Retracted Article) [J].