Circadian clocks regulate cardiac arrhythmia susceptibility, repolarization, and ion channels

Delisle, Brian P.; Stumpf, John L; Wayland, Jennifer L; Johnson, Sidney R.; Ono, Masafumi; Hall, Dalton; Burgess, Don E.; Schroder, Elizabeth A.

doi:10.1016/j.coph.2020.09.015

Cited by 11 publications

(13 citation statements)

References 79 publications

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“…This might not have been expected in mice with the ΔKPQ- Scn5a mutation since previous studies show that inducing the deletion of Bmal1 in adult cardiomyocytes decreases the functional expression of Scn5a by ∼30% ( Schroder et al, 2013 ). We now show that Bmal1 directly or indirectly contributes to the expression of many different cardiac transcripts that regulate normal depolarization, repolarization and conduction in mice ( Figure 1 ; Jeyaraj et al, 2012 ; Schroder et al, 2015 ; Delisle et al, 2020 ). Thus, the cardiac electrophysiological properties likely do not reflect the changes in one gene but rather many different genes.…”

Section: Discussionmentioning

confidence: 63%

“…In addition to functioning as ubiquitous cellular timekeepers, circadian clocks also contribute to cell- and tissue-specific changes in physiology by regulating the expression of genes outside the timekeeping network. Studies using transgenic mouse models that allow for the selective deletion of Bmal1 in adult cardiomyocytes show the cardiomyocyte circadian clock mechanism contributes to heart rate, ventricular repolarization and the functional expression of several cardiac ion channels ( Schroder et al, 2013 , 2015 ; Delisle et al, 2020 ). In this study, we determined how inducing the deletion of Bmal1 in adult cardiomyocytes impacted cardiac electrophysiology in a genetic mouse model of long QT syndrome (LQTS).…”

Section: Introductionmentioning

confidence: 99%

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Cardiomyocyte Deletion of Bmal1 Exacerbates QT- and RR-Interval Prolongation in Scn5a+/ΔKPQ Mice

et al. 2021

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Circadian rhythms are generated by cell autonomous circadian clocks that perform a ubiquitous cellular time-keeping function and cell type-specific functions important for normal physiology. Studies show inducing the deletion of the core circadian clock transcription factor Bmal1 in adult mouse cardiomyocytes disrupts cardiac circadian clock function, cardiac ion channel expression, slows heart rate, and prolongs the QT-interval at slow heart rates. This study determined how inducing the deletion of Bmal1 in adult cardiomyocytes impacted the in vivo electrophysiological phenotype of a knock-in mouse model for the arrhythmogenic long QT syndrome (Scn5a+/ΔKPQ). Electrocardiographic telemetry showed inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ-Scn5a mutation increased the QT-interval at RR-intervals that were ≥130 ms. Inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ-Scn5a mutation also increased the day/night rhythm-adjusted mean in the RR-interval, but it did not change the period, phase or amplitude. Compared to mice without the ΔKPQ-Scn5a mutation, mice with the ΔKPQ-Scn5a mutation had reduced heart rate variability (HRV) during the peak of the day/night rhythm in the RR-interval. Inducing the deletion of Bmal1 in cardiomyocytes did not affect HRV in mice without the ΔKPQ-Scn5a mutation, but it did increase HRV in mice with the ΔKPQ-Scn5a mutation. The data demonstrate that deleting Bmal1 in cardiomyocytes exacerbates QT- and RR-interval prolongation in mice with the ΔKPQ-Scn5a mutation.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Cardiomyocyte Deletion of Bmal1 Exacerbates QT- and RR-Interval Prolongation in Scn5a+/ΔKPQ Mice

et al. 2021

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“…The free-running 24 h oscillation in the mRNA transcript levels for these proteins was lost in the hearts of iCS Bmal1 -/mice, and ventricular cardiomyocytes isolated from these mice had smaller macroscopic I Na and I Kr . Heterologous expression assays designed to assess human promoter activity using cloned SCN5A or KCNH2 promoters that drive the expression of luciferase demonstrated that the SCN5A or KCNH2 promoters were transactivated by overexpression of BMAL1 and CLOCK, and the SCN5A and KCNH2 promoters showed circadian luciferase activity in cells using real-time bioluminescence recordings (Delisle, Stumpf et al, 2021;Schroder et al, 2013Schroder et al, , 2015.…”

Section: Cardiomyocyte Circadian Clocks Regulate Cardiac Ion Channel ...mentioning

confidence: 99%

The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology

Schroder

Ono

Johnson

et al. 2022

The Journal of Physiology

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Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24 h changes in the environment, behaviour and internal circadian rhythms. This article focuses on studies that use animal models to separate the impact that circadian rhythms, as well as changes in the environment and behaviour, have on 24 h rhythms in heart rate and ventricular repolarization. Circadian rhythms are initiated at the cellular level by circadian clocks, transcription–translation feedback loops that cycle with a periodicity of 24 h. Several studies now show that the circadian clock in cardiomyocytes regulates the expression of cardiac ion channels by multiple mechanisms; underlies time‐of‐day changes in sinoatrial node excitability/intrinsic heart rate; and limits the duration of the ventricular action potential waveform. However, the 24 h rhythms in heart rate and ventricular repolarization are primarily driven by autonomic signalling. A functional role for the cardiomyocyte circadian clock appears to buffer the heart against perturbations. For example, the cardiomyocyte circadian clock limits QT‐interval prolongation (especially at slower heart rates), and it may facilitate the realignment of the 24 h rhythm in heart rate to abrupt changes in the light cycle. Additional studies show that modifying rhythmic behaviours (including feeding behaviour) can dramatically impact the 24 h rhythms in heart rate and ventricular repolarization. If these mechanisms are conserved, these studies suggest that targeting endogenous circadian mechanisms in the heart, as well as modifying the timing of certain rhythmic behaviours, could emerge as therapeutic strategies to support heart function against perturbations and regulate 24 h rhythms in cardiac electrophysiology.

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“…One question of great interest is the circadian mechanisms in SCD, the topic of a recent workshop, “Understanding Circadian Mechanisms of Sudden Cardiac Death”, convened by the National Institutes of Health, USA (accessed on 11 June 2021). Acquired or hereditary heart diseases are the leading cause of SCD, and the primary mechanism leading to SCD is cardiac arrhythmias, particularly ventricular arrhythmias [ 18 , 19 , 20 ]. In the heart, membrane depolarization (sodium and calcium channels) and repolarization (potassium channels) are tightly regulated to maintain normal action potential, and adverse events causing exaggerated depolarization or diminished repolarization can disrupt the balance, increasing the risk of arrhythmias and ultimately SCD [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Its oscillatory amplitude and expression levels were considerably reduced in iCSΔBmal1 mice, leading to attenuated Na+ current in ventricular myocytes [ 22 ]. Likewise, repolarization has also been shown to be subjected to circadian control [ 18 , 19 ]. For example, the transcription factor Krupple-like factor 15 (KLF15) is a CLOCK/BMAL1 target gene containing several E-box elements in its promoter region [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine

et al. 2021

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Dysregulated circadian functions contribute to various diseases, including cardiovascular disease. Much progress has been made on chronotherapeutic applications of drugs against cardiovascular disease (CVD); however, the direct effects of various medications on the circadian system are not well characterized. We previously conducted high-throughput chemical screening for clock modulators and identified an off-patent anti-arrhythmic drug, moricizine, as a clock-period lengthening compound. In Per2:LucSV reporter fibroblast cells, we showed that under both dexamethasone and forskolin synchronization, moricizine was able to increase the circadian period length, with greater effects seen with the former. Titration studies revealed a dose-dependent effect of moricizine to lengthen the period. In contrast, flecainide, another Class I anti-arrhythmic, showed no effects on circadian reporter rhythms. Real-time qPCR analysis in fibroblast cells treated with moricizine revealed significant circadian time- and/or treatment-dependent expression changes in core clock genes, consistent with the above period-lengthening effects. Several clock-controlled cardiac channel genes also displayed altered expression patterns. Using tissue explant culture, we showed that moricizine was able to significantly prolong the period length of circadian reporter rhythms in atrial ex vivo cultures. Using wild-type C57BL/6J mice, moricizine treatment was found to promote sleep, alter circadian gene expression in the heart, and show a slight trend of increasing free-running periods. Together, these observations demonstrate novel clock-modulating activities of moricizine, particularly the period-lengthening effects on cellular oscillators, which may have clinical relevance against heart diseases.

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Circadian clocks regulate cardiac arrhythmia susceptibility, repolarization, and ion channels

Cited by 11 publications

References 79 publications

Cardiomyocyte Deletion of Bmal1 Exacerbates QT- and RR-Interval Prolongation in Scn5a+/ΔKPQ Mice

Cardiomyocyte Deletion of Bmal1 Exacerbates QT- and RR-Interval Prolongation in Scn5a+/ΔKPQ Mice

The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology

Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine

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