Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility

Abstract

RATIONALE: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the early 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. OBJECTIVE: The objectives are to investigate the recruitment of transcription factors to time-of-day differentially accessible chromatin that underpins day-night ion channel rhythms and to assess the significance of this for the heart’s day-night rhythm in VA susceptibility. METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the inactive (zeitgeber time, time of lights on, start of sleep period) and active (time of lights off, start of awake period [ZT12]) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) binding site 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.

Circadian-Regulated GR Signaling Mediates Morning Arrhythmias

“…14 Based on this knowledge, the authors confirmed that GRs can bind and modulate transcriptional targets of I Na and I Kr in a time-of-daydependent chromatin accessibility. 9 Another intriguing finding in this study was that GRs can indirectly regulate the rhythmic transcription of Gja1, a gap junction channel gene responsible for electrical coupling. By using 2 different GR knockout models (GR fl/fl and cardioGRKO), the authors demonstrated that the daily variation of Gja1 was abolished, which was also associated with the loss of increased vulnerability to VA at the active phase, perhaps due to functional loss of the day/night rhythm in electrical coupling.…”

“…However, despite these compelling findings, a new study by Tikhomirov et al, published in this issue of Circulation Research, suggests that the simple dimerization model of CLOCK and BMAL1 proteins binding to their cognate ion channel promoters may alone be insufficient to explain circadian-dependent occurrence of VA. In fact, this study points to a new and intriguing concept that suggests that changes in chromatin reorganization may be a critical event underlying the circadian rhythmicity of arrhythmias 9 Next, the authors aimed to identify TFs that may be involved in rhythmic gene expression patterns, which could explain the daily changes in ventricular electrical excitability. GRs (glucocorticoid receptors) were identified as a candidate TF with increased transcription at ZT12.…”

“…By using 2 different GR knockout models (GR fl/fl and cardioGRKO), the authors demonstrated that the daily variation of Gja1 was abolished, which was also associated with the loss of increased vulnerability to VA at the active phase, perhaps due to functional loss of the day/night rhythm in electrical coupling. 9 In composite, the study by Tikhomirov et al demonstrates for the first time that in preparation for the active phase, GRs respond to hormonal signals, such as glucocorticoids, resulting in dramatic changes to electrophysiological properties in the heart. Therefore, this study strongly suggests that chromatin-accessible ion channels and gap junction genes and their functional regulation may be a key underlying mechanism of VA in the morning hours.…”