D'Souza, A;
Wang, Y;
Anderson, C;
Bucchi, A;
Barsucotti, M;
Olieslagers, S;
Mesirca, P;
... Boyett, MR; + view all
(2020)
A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate.
Heart Rhythm
10.1016/j.hrthm.2020.11.026.
(In press).
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Abstract
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 ECG recordings, vagotomy, transgenics, quantitative polymerase chain reaction, western blotting, immunohistochemistry, patch clamp, 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 (i.e. denervated) sinus node (SN) preparations exhibited a day-night rhythm concomitant with rhythmic mRNA expression of ion channels including HCN4. In vitro studies demonstrated 24 h 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 factors, e.g. Bmal1 and Cry, were identified in the SN and disruption of the local clock (by cardiac-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. / Conclusion: 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.
| Type: | Article |
|---|---|
| Title: | A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.hrthm.2020.11.026 |
| Publisher version: | https://doi.org/10.1016/j.hrthm.2020.11.026 |
| Language: | English |
| Additional information: | This is an open access article under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
| Keywords: | Circadian rhythm, Nocturnal bradycardia, Pacemaking, Sinus node, Vagus nerve |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10116835 |
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