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Fletcher EK, Kanki M, Morgan J, et al. Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling. J Endocrinol. 2019;doi: 10.1530/JOE-18-0584.
Fletcher, E. K., Kanki, M., Morgan, J., Ray, D. W., Delbridge, L., Fuller, P. J., Clyne, C. D., & Young, M. J. (2019). Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling. The Journal of endocrinology, . https://doi.org/10.1530/JOE-18-0584
Fletcher, ELizabeth K, et al. "Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling." The Journal of endocrinology vol. (2019). doi: https://doi.org/10.1530/JOE-18-0584
Fletcher EK, Kanki M, Morgan J, Ray DW, Delbridge L, Fuller PJ, Clyne CD, Young MJ. Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling. J Endocrinol. 2019 Jan 01; doi: 10.1530/JOE-18-0584. Epub 2019 Jan 01. PMID: 30689544.
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J Endocrinol. 2019 Jan 01; doi: 10.1530/JOE-18-0584. Epub 2019 Jan 01.

Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling.

The Journal of endocrinology

ELizabeth K Fletcher, Monica Kanki, James Morgan, David W Ray, Lea Delbridge, Peter James Fuller, Colin D Clyne, Morag J Young

Affiliations

  1. E Fletcher, Sackler School of Graduate Biomedical Sciences, Tuft Medical Centre, Boston, United States.
  2. M Kanki, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Australia.
  3. J Morgan, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Australia.
  4. D Ray, Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom of Great Britain and Northern Ireland.
  5. L Delbridge, Dept Of Physiology, University of Melbourne, Melbourne, xxx, Australia.
  6. P Fuller, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Australia.
  7. C Clyne , Cancer Drug Discovery, Hudson Institute of Medical Research, Clayton, Australia.
  8. M Young, Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, 3166, Australia.

PMID: 30689544 DOI: 10.1530/JOE-18-0584

Abstract

We previously identified a critical pathogenic role for MR activation in cardiomyocytes that included a potential interaction between the MR and the molecular circadian clock. While glucocorticoid regulation of the circadian clock is undisputed, MR interactions with circadian clock signalling are limited. We hypothesised that the MR influences cardiac circadian clock signalling, and vice versa. 10nM aldosterone or corticosterone regulated CRY 1, PER1, PER2 and ReverbA (NR1D1) gene expression patterns in H9c2 cells over 24hr. MR-dependent regulation of circadian gene promoters containing GREs and E-box sequences was established for CLOCK, Bmal, CRY 1 and CRY2, PER1 and PER2 and transcriptional activators CLOCK and Bmal modulated MR-dependent transcription of a subset of these promoters. We also demonstrated differential regulation of MR target gene expression in hearts of mice 4hr after administration of aldosterone at 8AM versus 8PM. Our data support combined MR regulation of a subset of circadian genes and that endogenous circadian transcription factors CLOCK and Bmal modulate this response. This unsuspected relationship links MR in the heart to circadian rhythmicity at the molecular level and has important implications for the biology of MR signalling in response to aldosterone as well as cortisol. These data are consistent with MR signalling in the brain where, like the heart, it preferentially responds to cortisol. Given the undisputed requirement for diurnal cortisol release in the entrainment of peripheral clocks, the present study highlights the MR as an important mechanism for transducing the circadian actions of cortisol in addition to the GR in the heart.

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