7763 Mineralocorticoid Receptor Regulation of the Molecular Clock in Cardiomyocytes Is Modulated by Time of Day

Abstract Disclosure: M. Kanki: None. S. Heanue: None. P.J. Fuller: None. T.J. Cole: None. C.D. Clyne: None. M.J. Young: None. The onset of cardiovascular disease events peaks in the early morning, which coincides with the diurnal surge in aldosterone and cortisol. Aldosterone-induced mineralocorticoid receptor (MR) activation in cardiomyocytes has established roles in cardiac pump function and electrophysiology and inappropriate MR activation promotes cardiovascular pathophysiology in experimental models of hypertension and heart failure and in the clinic. Recently, we identified a novel role for MR in regulating the circadian clock signalling network in cardiac cells and showed that time of day modulates MR activation in the heart. Whether time-of-day-dependent MR regulation of circadian clocks in cardiomyocytes modulates temporal expression of key functional pathways is unknown. Therefore, we sought to identify cardiac responsiveness to MR stimulation at lights on (7AM) versus lights off (7PM) in ≥8-week old male wildtype (WT) and cardiomyocyte-MR knockout (MyoMRKO) mice. RNA-seq analyses revealed that aldosterone (50 ug/kg) administered at 7PM but not at 7AM significantly enriched transcription of genes associated with 52 biological processes including “Circadian rhythm”, “Reg. of blood pressure”, “Ion transport” and “Reg. of the force of heart contraction” in WT hearts (p<0.05 versus 7PM vehicle-injected WT mice). These outcomes were absent in hearts isolated from MyoMRKO mice administered aldosterone at 7AM or 7PM. Analysis by RT-qPCR revealed that aldosterone versus vehicle administered at 7AM increased expression of circadian Period (Per) and Thyrotroph embryonic factor (Tef) genes in WT hearts, which was lost in MyoMRKO mice. Whole transcriptome analysis also detected significant enrichment in “Cell-cell signalling”, “Positive regulation of cell differentiation”, “Positive regulation of glucose metabolic process”, “Regulation of sodium ion transport”, and “Inflammatory response" processes between 7AM and 7PM in WT hearts, which was also lost in MyoMRKO mice. Our data show that MR transcription of genes associated with circadian rhythms and ion transport is temporally regulated, and demonstrates specificity for cardiomyocyte-MR regulation of circadian clocks. Taken together, we highlight that the role for cardiomyocyte-MR regulation of cardiac electrophysiology, heart rate variability, and metabolic processes is time-of-day-dependent. Understanding temporal coordination of MR activation in physiology and pathophysiology may inform new strategies for optimising MR-directed therapies in patients with heart disease. Presentation: 6/2/2024