The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility

Elizabeth A. Schroder, Mellani Lefta, Xiping Zhang, Daniel Bartos, Han Zhong Feng, Yihua Zhao, Abhijit Patwardhan, Jian Ping Jin, Karyn A. Esser, Brian P. Delisle

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1-/-) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCSΔBmal1-/- hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na+ channel (NaV1.5), was circadianly expressed in control mouse and rat hearts but not in iCSΔBmal1-/- hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCSΔBmal1-/- hearts was associated with decreased levels of NaV1.5 and Na+ current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans.

Original languageEnglish
Pages (from-to)C954-C965
JournalAmerican Journal of Physiology - Cell Physiology
Volume304
Issue number10
DOIs
StatePublished - May 15 2013

Keywords

  • Cardiac excitability
  • Circadian
  • Heart
  • Ion channels
  • Na cur-rent
  • Scn5a

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Fingerprint

Dive into the research topics of 'The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility'. Together they form a unique fingerprint.

Cite this