The Cardiomyocyte Molecular Clock Regulates the Circadian Expression of Kcnh2 and Contributes to Ventricular Repolarization

Overview

Journal Heart Rhythm

Publisher Elsevier

Specialty Cardiology & Vascular Diseases

Date 2015 Feb 22

PMID 25701773

Citations 49

Authors

Elizabeth A Schroder

Don E Burgess

Xiping Zhang

Mellani Lefta

Jennifer L Smith

Abhijit Patwardhan

Daniel C Bartos

Claude S Elayi

Karyn A Esser

Brian P Delisle

Affiliations

Soon will be listed here.

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.

Conclusion: 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.

Citing Articles

Morning physical activity may be more beneficial for blood lipids than afternoon physical activity in older adults: a cross-sectional study.

Kim H, Kimura Y, Takahashi M, Nakaoka T, Yamada Y, Ono R Eur J Appl Physiol. 2024; 124(11):3253-3263.

PMID: 38874620 PMC: 11519190. DOI: 10.1007/s00421-024-05526-y.

Feeding behavior modifies the circadian variation in RR and QT intervals by distinct mechanisms in mice.

Ono M, Burgess D, Johnson S, Elayi C, Esser K, Seward T Am J Physiol Regul Integr Comp Physiol. 2024; 327(1):R109-R121.

PMID: 38766772 PMC: 11380991. DOI: 10.1152/ajpregu.00025.2024.

Research progress of circadian rhythm in cardiovascular disease: A bibliometric study from 2002 to 2022.

Tian H, Zhao X, Zhang Y, Xia Z Heliyon. 2024; 10(7):e28738.

PMID: 38560247 PMC: 10979111. DOI: 10.1016/j.heliyon.2024.e28738.

Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.

Tikhomirov R, Oakley R, Anderson C, Xiang Y, Al-Othman S, Smith M Circ Res. 2024; 134(10):1306-1326.

PMID: 38533639 PMC: 11081863. DOI: 10.1161/CIRCRESAHA.123.323464.

Circadian Regulation of Cardiac Arrhythmias and Electrophysiology.

Delisle B, Prabhat A, Burgess D, Ono M, Esser K, Schroder E Circ Res. 2024; 134(6):659-674.

PMID: 38484028 PMC: 11177776. DOI: 10.1161/CIRCRESAHA.123.323513.

References

Durgan D, Hotze M, Tomlin T, Egbejimi O, Graveleau C, Abel E . The intrinsic circadian clock within the cardiomyocyte. Am J Physiol Heart Circ Physiol. 2005; 289(4):H1530-41. DOI: 10.1152/ajpheart.00406.2005. View

Young M, Razeghi P, Taegtmeyer H . Clock genes in the heart: characterization and attenuation with hypertrophy. Circ Res. 2001; 88(11):1142-50. DOI: 10.1161/hh1101.091190. View

Yamashita T, Sekiguchi A, Iwasaki Y, Sagara K, Iinuma H, Hatano S . Circadian variation of cardiac K+ channel gene expression. Circulation. 2003; 107(14):1917-22. DOI: 10.1161/01.CIR.0000058752.79734.F0. View

Muller J, Ludmer P, Willich S, Tofler G, Aylmer G, Klangos I . Circadian variation in the frequency of sudden cardiac death. Circulation. 1987; 75(1):131-8. DOI: 10.1161/01.cir.75.1.131. View

Willich S, Levy D, Rocco M, Tofler G, Stone P, Muller J . Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol. 1987; 60(10):801-6. DOI: 10.1016/0002-9149(87)91027-7. View

Merri M, MOSS A, Benhorin J, Locati E, Alberti M, Badilini F . Relation between ventricular repolarization duration and cardiac cycle length during 24-hour Holter recordings. Findings in normal patients and patients with long QT syndrome. Circulation. 1992; 85(5):1816-21. DOI: 10.1161/01.cir.85.5.1816. View

Sanguinetti M, Jiang C, Curran M, Keating M . A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995; 81(2):299-307. DOI: 10.1016/0092-8674(95)90340-2. View

Mitchell G, Jeron A, Koren G . Measurement of heart rate and Q-T interval in the conscious mouse. Am J Physiol. 1998; 274(3):H747-51. DOI: 10.1152/ajpheart.1998.274.3.H747. View

Zhang S . Isolation and characterization of I(Kr) in cardiac myocytes by Cs+ permeation. Am J Physiol Heart Circ Physiol. 2005; 290(3):H1038-49. DOI: 10.1152/ajpheart.00679.2005. View

10.

Sanguinetti M, Tristani-Firouzi M . hERG potassium channels and cardiac arrhythmia. Nature. 2006; 440(7083):463-9. DOI: 10.1038/nature04710. View

11.

Guo J, Massaeli H, Li W, Xu J, Luo T, Shaw J . Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes. J Pharmacol Exp Ther. 2007; 321(3):911-20. DOI: 10.1124/jpet.107.120931. View

12.

Bray M, Shaw C, Moore M, Garcia R, Zanquetta M, Durgan D . Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am J Physiol Heart Circ Physiol. 2007; 294(2):H1036-47. DOI: 10.1152/ajpheart.01291.2007. View

13.

Guo J, Massaeli H, Xu J, Jia Z, Wigle J, Mesaeli N . Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines. J Clin Invest. 2009; 119(9):2745-57. PMC: 2735921. DOI: 10.1172/JCI39027. View

14.

Martino T, Sole M . Molecular time: an often overlooked dimension to cardiovascular disease. Circ Res. 2009; 105(11):1047-61. DOI: 10.1161/CIRCRESAHA.109.206201. View

15.

Hughes M, Hogenesch J, Kornacker K . JTK_CYCLE: an efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets. J Biol Rhythms. 2010; 25(5):372-80. PMC: 3119870. DOI: 10.1177/0748730410379711. View

16.

Zhang E, Kay S . Clocks not winding down: unravelling circadian networks. Nat Rev Mol Cell Biol. 2010; 11(11):764-76. DOI: 10.1038/nrm2995. View

17.

Jeyaraj D, Haldar S, Wan X, McCauley M, Ripperger J, Hu K . Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature. 2012; 483(7387):96-9. PMC: 3297978. DOI: 10.1038/nature10852. View

18.

Zhang X, Patel S, McCarthy J, Rabchevsky A, Goldhamer D, Esser K . A non-canonical E-box within the MyoD core enhancer is necessary for circadian expression in skeletal muscle. Nucleic Acids Res. 2012; 40(8):3419-30. PMC: 3333858. DOI: 10.1093/nar/gkr1297. View

19.

Mohawk J, Green C, Takahashi J . Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012; 35:445-62. PMC: 3710582. DOI: 10.1146/annurev-neuro-060909-153128. View

20.

Pizarro A, Hayer K, Lahens N, Hogenesch J . CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res. 2012; 41(Database issue):D1009-13. PMC: 3531170. DOI: 10.1093/nar/gks1161. View