The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility.
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 (Na(V)1.5), 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 Na(V)1.5 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.
Center for Muscle Biology, University of Kentucky, Lexington, KY 40536, USA. eschr0@uky.edu
Elizabeth A
EA
Schroder
Mellani
M
Lefta
Xiping
X
Zhang
Daniel C
DC
Bartos
Han-Zhong
HZ
Feng
Yihua
Y
Zhao
Abhijit
A
Patwardhan
Jian-Ping
JP
Jin
Karyn A
KA
Esser
Brian P
BP
Delisle
D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D001683:Biological Clocks; D001794:Blood Pressure / Q000235:genetics; D009202:Cardiomyopathies / Q000235:genetics; D002460:Cell Line; D002940:Circadian Rhythm; D017353:Gene Deletion; D006339:Heart Rate / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011921:Rats, Inbred WKY
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse
Na+ current; Scn5a; cardiac excitability; circadian; heart; ion channels