title: The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization.
abstract: BACKGROUND
  Sudden cardiac death (SCD) follows a diurnal variation. Data suggest the timing of SCD is influenced by circadian (~24-hour) changes in neurohumoral and cardiomyocyte-specific regulation of the heart's electrical properties. The basic helix-loop-helix transcription factors brain muscle arnt-like1 (BMAL1) and circadian locomotor output control kaput (CLOCK) coordinate the circadian expression of select genes.
  
  
  OBJECTIVE
  We sought to test whether Bmal1 expression in cardiomyocytes contributes to K(+) channel expression and diurnal changes in ventricular repolarization.
  
  
  METHODS
  We used transgenic mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1(-/-)). We used quantitative polymerase chain reaction, voltage clamping, promoter-reporter bioluminescence assays, and electrocardiographic telemetry.
  
  
  RESULTS
  Although several K(+) channel gene transcripts were downregulated in iCSΔBmal1(-/-)mouse hearts, only Kcnh2 exhibited a robust circadian pattern of expression that was disrupted in iCSΔBmal1(-/-) hearts. Kcnh2 underlies the rapidly activating delayed-rectifier K(+) current, and the rapidly activating delayed-rectifier K(+) current recorded from iCSΔBmal1(-/-) ventricular cardiomyocytes was ~50% smaller than control ventricular myocytes. Promoter-reporter assays demonstrated that the human Kcnh2 promoter is transactivated by the coexpression of BMAL1 and CLOCK. Electrocardiographic analysis showed that iCSΔBmal1(-/-) mice developed a prolongation in the heart rate-corrected QT interval during the light (resting) phase. This was secondary to an augmented circadian rhythm in the uncorrected QT interval without a corresponding change in the RR interval.
  
  
  CONCLUSIONS
  The molecular clock in the heart regulates the circadian expression of Kcnh2, modifies K(+) channel gene expression, and is important for normal ventricular repolarization. Disruption of the cardiomyocyte circadian clock mechanism likely unmasks diurnal changes in ventricular repolarization that could contribute to an increased risk of cardiac arrhythmias/SCD.
authors.affiliation: Center for Muscle Biology, Department of Physiology.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schroder
authors.affiliation: Center for Muscle Biology, Department of Physiology.
authors.forename: Don E
authors.initials: DE
authors.lastname: Burgess
authors.affiliation: Center for Muscle Biology, Department of Physiology.
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Muscle Biology, Department of Physiology.
authors.forename: Mellani
authors.initials: M
authors.lastname: Lefta
authors.affiliation: Center for Muscle Biology, Department of Physiology.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Smith
authors.affiliation: Center for Biomedical Engineering.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Patwardhan
authors.affiliation: Center for Muscle Biology, Department of Physiology.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bartos
authors.affiliation: Department of Cardiology, University of Kentucky, Lexington, Kentucky.
authors.forename: Claude S
authors.initials: CS
authors.lastname: Elayi
authors.affiliation: Center for Muscle Biology, Department of Physiology.
authors.forename: Karyn A
authors.initials: KA
authors.lastname: Esser
authors.affiliation: Center for Muscle Biology, Department of Physiology.. Electronic address: brian.delisle@uky.edu.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D003001:Cloning, Molecular; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D015870:Gene Expression; D006339:Heart Rate / Q000502:physiology; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*; D015221:Potassium Channels / Q000032:analysis* / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C000606915:Kcnh2 protein, mouse; D015221:Potassium Channels
keywords: Bmal1; Circadian rhythm; ECG; Kcnh2; QTc; Repolarization