A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate.
Bradycardia
Circadian rhythm
Pacemaking
Sinus node
Vagus nerve
Journal
Heart rhythm
ISSN: 1556-3871
Titre abrégé: Heart Rhythm
Pays: United States
ID NLM: 101200317
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
05
05
2020
revised:
09
11
2020
accepted:
21
11
2020
pubmed:
6
12
2020
medline:
19
1
2022
entrez:
5
12
2020
Statut:
ppublish
Résumé
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.
Sections du résumé
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 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 (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.
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.
Identifiants
pubmed: 33278629
pii: S1547-5271(20)31130-9
doi: 10.1016/j.hrthm.2020.11.026
pmc: PMC8073545
pii:
doi:
Substances chimiques
Hcn4 protein, mouse
0
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
801-810Subventions
Organisme : British Heart Foundation
ID : FS/19/1/34035
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/11/18/29257
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/J003441
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/15/16/31330
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.