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 factors, for example, Bmal1 and Cry, was 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.

A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate / A. D'Souza, Y. Wang, C. Anderson, A. Bucchi, M. Baruscotti, S. Olieslagers, P. Mesirca, A.B. Johnsen, S. Mastitskaya, H. Ni, Y. Zhang, N.B. BmBCh, C. Cox, S. Wegner, B. Bano-Otalora, C. Petit, E. Gill, S.J. Logantha, H. Dobrzynski, N. Ashton, G. Hart, R. Zhang, H. Zhang, E.J. Cartwright, U. Wisloff, M.E. Mangoni, P. Da Costa Martins, H.D. Piggins, D. DiFrancesco, M.R. Boyett. - In: HEART RHYTHM. - ISSN 1547-5271. - 18:5(2021), pp. 801-810.

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

A. Bucchi;M. Baruscotti;D. DiFrancesco;
2021

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 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 factors, for example, Bmal1 and Cry, was 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.
Circadian rhythm; Nocturnal bradycardia; Pacemaking; Sinus node; Vagus nerve
Settore BIO/09 - Fisiologia
2021
3-dic-2020
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S1547527120311309-main.pdf

Open Access dal 04/12/2021

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 2.39 MB
Formato Adobe PDF
2.39 MB Adobe PDF Visualizza/Apri
PIIS1547527120311309.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 2.17 MB
Formato Adobe PDF
2.17 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/806083
Citazioni
  • ???jsp.display-item.citation.pmc??? 25
  • Scopus 44
  • ???jsp.display-item.citation.isi??? 41
social impact