Circadian Regulation of Cardiac Physiology: Rhythms That Keep the Heart Beating

Abstract

On Earth, all life is exposed to dramatic changes in the environment over the course of the day; consequently, organisms have evolved strategies to both adapt to and anticipate these 24-h oscillations. As a result, time of day is a major regulator of mammalian physiology and processes, including transcription, signaling, metabolism, and muscle contraction, all of which oscillate over the course of the day. In particular, the heart is subject to wide fluctuations in energetic demand throughout the day as a result of waking, physical activity, and food intake patterns. Daily rhythms in cardiovascular function ensure that increased delivery of oxygen, nutrients, and endocrine factors to organs during the active period and the removal of metabolic by-products are in balance. Failure to maintain these physiologic rhythms invariably has pathologic consequences. This review highlights rhythms that underpin cardiac physiology. More specifically, we summarize the key aspects of cardiac physiology that oscillate over the course of the day and discuss potential mechanisms that regulate these 24-h rhythms.

Keywords: chronobiology; heart; mitochondrial quality control; posttranslational modification; redox biology.

Figure 1.

A) Functions of Caesin Kinase (CK) 1d/e in the mammalian clock. A) Interaction with CRY stabilizes PER, allowing it be phosphorylated by leading to its nuclear translocation and repression of Clock/Bmal1 transcription; B) CK1δ/ε phosphorylation of PER in the cytosol leads to proteasomal degradation; C) CK1 δ/ε phosphorylation of Bmal1 increases its transcriptional activity. B) Cross-talk between phosphorylation (P) and O-GlcNAcylation (G) in the regulation of the circadian clock. GSK3β phosphorylation of OGT results in its activation, leading to O-GlcNAcylation of PER and CRY, which prevents their phosphorylation thereby repressing their effects on CLOCK/BMAL1 transcription. O-GlcNAcylation of CLOCK also represses the effects of PER. Phosphorylation and O-GlcNAcylation also play a role in regulating the ubiquitination and subsequent degradation of CLOCK and BMAL1

Figure 2.. Crosstalk between circadian clock components and reactive species.

Both reactive species and antioxidants are circadian regulated. Moreover, the activities of circadian clock components can also be modulated by reactive species. To what extent this cross talk occurs in the heart requires full elucidation.

Figure 3.. Circadian regulation of genes influencing mitochondrial function and morphology.

Mitochondrial respiration generally peaks early in the active period, while autophagy/mitophagy peaks during inactive period, presumably ensuring mitochondrial remodeling and quality control. Oscillation of mRNAs encoding mitochondrial electron transport chain (ETC) proteins, fission protein Drp1, and Akt1/2, as well and autophagy adaptor protein sequestosome1/p62 are controlled by BMAL1 and CLOCK in the heart. However, whether mitophagic flux is higher in the inactive phase remains unclear. How regulation of mitochondrial function, dynamics and quality control by circadian clock contributes to cardiac physiology and pathology is an important question to be address.