Circadian and infradian rhythms of cardiac L-type Ca2+ channel transcription

Abstract

Cardiac function shows chronobiological regulation, controlled by both central and endogenous clocks that might be impaired in pathological conditions, in which Ca 2+ homeostasis plays a critical role. The L-type calcium channels, whose pore is formed by the Cav1.2 subunit, are the main mediators of Ca 2+ influx of ventricular cardiomyocytes participating to cardiac electrical activity, contraction and gene expression. Thus, the study of rhythm in the dynamics of Cav1.2 expression is of importance. To address this question, 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 Cav1.2 cardiac promoter. Under normal light/dark cycle, we observed a circadian oscillation in the Cav1.2 promoter activity with two similar cycles that peak at ZT9 and ZT18. Monitoring circadian rhythms (CR) of bioluminescence in isolated ventricular cardiomyocytes will be used to determine whether these variations are generated or not by endogenous circadian clock mechanisms. Surprisingly, our analysis also revealed an unprecedented infradian (multi-day) rhythms on top of CR. Over 2 months analysis, recording BLI twice a week at ZT1 in the same mice, we observed a ∼20-day period of the Cav1.2 cardiac promoter activity, during which the BLI might present more than 200% variation. Our innovative study provides new insights into the temporal dynamic of cardiac L-type Ca 2+ channel transcription control, which oscillate not only over the course of the day, that might have an impact in cardiac physiopathology.