Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.

Autor:	Tikhomirov R; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom.; Myocardial Function Section, National Heart and Lung Institute, Imperial College London, United Kingdom (R.T., M.S., A.D.)., Oakley RH; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)., Anderson C; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom., Xiang Y; Department of Physics and Astronomy (Y.X., H.Z.), The University of Manchester, United Kingdom., Al-Othman S; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom., Smith M; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom.; Myocardial Function Section, National Heart and Lung Institute, Imperial College London, United Kingdom (R.T., M.S., A.D.)., Yaar S; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom., Torre E; Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), F-34094 Montpellier France (E.T., P.M., M.E.M.)., Li J; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)., Wilson LR; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)., Goulding DR; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)., Donaldson I; Bioinformatics Core Facility (I.D.), The University of Manchester, United Kingdom., Harno E; Division of Diabetes, Endocrinology and Gastroenterology (E.H.), The University of Manchester, United Kingdom., Soattin L; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom., Shiels HA; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom., Morris GM; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom.; Department of Cardiology, John Hunter Hospital, Newcastle, NSW, Australia (G.M.M.)., Zhang H; Department of Physics and Astronomy (Y.X., H.Z.), The University of Manchester, United Kingdom., Boyett MR; Faculty of Life Sciences, University of Bradford, United Kingdom (M.R.B.)., Cidlowski JA; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (R.H.O., J.L., L.R.W., D.R.G., J.A.C.)., Mesirca P; Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), F-34094 Montpellier France (E.T., P.M., M.E.M.)., Mangoni ME; Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), F-34094 Montpellier France (E.T., P.M., M.E.M.)., D'Souza A; Division of Cardiovascular Sciences (R.T., C.A., S.A.O., M.S., S.Y., L.S., H.A.S., G.M.M., A.D.), The University of Manchester, United Kingdom.; Myocardial Function Section, National Heart and Lung Institute, Imperial College London, United Kingdom (R.T., M.S., A.D.).
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2024 May 10; Vol. 134 (10), pp. 1306-1326. Date of Electronic Publication: 2024 Mar 27.
DOI:	10.1161/CIRCRESAHA.123.323464
Abstrakt:	Background: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional rhythms in ion channels and assessed whether this mechanism was pertinent to the heart's intrinsic diurnal susceptibility to VA. Methods and Results: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the animals' inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na + current, Kcnh2 underlying the rapid delayed rectifier K + current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts. Conclusions: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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