Circadian regulation of cardiac Cav1.2

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Diurnal variations in the ion channels that govern the excitation dynamics of cardiac cells may provide the crucial link between circadian clock and cardiac arrhythmias, a leading cause of cardiovascular death, which are more likely to occur in the morning after waking. These have been mainly related to circadian variations of K+ channels expression, but little is known about the the L-type calcium channels (LTCC), whose pore is formed by the Cav1.2 subunit and are the main mediators of Ca2+ influx of ventricular cardiomyocytes participating to cardiac electrical activity, contraction and gene expression. We aim to study the temporal dynamic of cardiac Cav1.2 expression. We monitored by in vivo bioluminescence (BLI) the Cav1.2 promoter activity using a transgenic male mouse model expressing luciferase under the control of the cardiac Cav1.2 promoter (PCa-luc mice). Under normal light:dark cycle, we observed a significant oscillation in the Cav1.2 promoter activity with a 1.5-fold increase at Zeitgeber time (ZT) 9 and 18. Coordinated oscillation of Cav1.2 mRNA level and its regulatory subunits (Cavβ2 and Cavα2δ1) is observed in mice ventricles during 24 hours with a peak at ZT12, along with classical oscillation of the actors of molecular clock machinery. Notably we noticed a clear relation between Cav1.2, CLOCK and REV-ERBa mRNA expression. Likewise, Cav1.2 protein expression showed significant circadian variations in mice ventricles, which peak at ZT12. A comparable circadian pattern of cardiac Cav1.2 promoter activity and gene transcripts (Cav1.2, Cavβ2 and α2δ1 and clock genes) was observed in isolated mice ventricular cardiomyocytes and in cardiomyocytes derived from human induced pluripotent stem cells, after serum shock synchronization. In addition, over 3 month in vivo BLI monitoring of PCa-Luc mice (recorded twice a week at ZT1), we observed a 2-fold variations of the Cav1.2 cardiac promoter activity, with a ∼16-day period. Collectively, our findings suggested that the cardiac LTCC is expressed rhythmically, peaking during rest to active period, in part under the intracardiac CLOCK-REV-ERba regulation, which might have an impact in cardiac physiopathology.