Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine.

Chorong Han,Marvin Wirianto,Mark J Burish,Zheng Chen,Eunju Kim,Seung-Hee Yoo

doi:10.3390/clockssleep3030022

Chorong Han, Marvin Wirianto + Show 4 more

Open Access

https://doi.org/10.3390/clockssleep3030022

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Abstract

Dysregulated circadian functions contribute to various diseases, including cardiovascular disease. Much progress has been made on chronotherapeutic applications of drugs against cardiovascular disease (CVD); however, the direct effects of various medications on the circadian system are not well characterized. We previously conducted high-throughput chemical screening for clock modulators and identified an off-patent anti-arrhythmic drug, moricizine, as a clock-period lengthening compound. In Per2:LucSV reporter fibroblast cells, we showed that under both dexamethasone and forskolin synchronization, moricizine was able to increase the circadian period length, with greater effects seen with the former. Titration studies revealed a dose-dependent effect of moricizine to lengthen the period. In contrast, flecainide, another Class I anti-arrhythmic, showed no effects on circadian reporter rhythms. Real-time qPCR analysis in fibroblast cells treated with moricizine revealed significant circadian time- and/or treatment-dependent expression changes in core clock genes, consistent with the above period-lengthening effects. Several clock-controlled cardiac channel genes also displayed altered expression patterns. Using tissue explant culture, we showed that moricizine was able to significantly prolong the period length of circadian reporter rhythms in atrial ex vivo cultures. Using wild-type C57BL/6J mice, moricizine treatment was found to promote sleep, alter circadian gene expression in the heart, and show a slight trend of increasing free-running periods. Together, these observations demonstrate novel clock-modulating activities of moricizine, particularly the period-lengthening effects on cellular oscillators, which may have clinical relevance against heart diseases.

Highlights

The mammalian circadian clock is our internal biological timer and plays a fundamental role in safeguarding health throughout our lifespan [1]
Several core clock genes were found to display altered circadian expression patterns consistent with period lengthening by moricizine
In accordance with core clock modulation, expression of several clock-controlled ion channel genes was changed in a circadian time-dependent manner

Summary

Introduction

The mammalian circadian clock is our internal biological timer and plays a fundamental role in safeguarding health throughout our lifespan [1]. In response to the daily cycles of environmental changes from Earth’s rotation, the clock anticipates and adapts by orchestrating cellular and physiological functions throughout our body. The functional component of the clock is the ubiquitous cell-autonomous oscillator, consisting of highly conserved, interlocked negative feedback loops containing positive (e.g., CLOCK/NPAS2, BMAL1, RORs) and negative (e.g., PERs, CRYs, REV-ERBs) constituents. These cellular oscillators govern clock-controlled gene (CCG) expression directly, by the aforementioned core components, or indirectly, via secondary regulatory factors [2]. Systemic profiling has revealed very modest overlap in CCGs (~10%) among different tissues [3,4], indicating local clocks function to regulate tissue physiology.

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