An overview of the emerging interface between cardiac metabolism, redox biology and the circadian clock

Abstract

At various biological levels, mammals must integrate with 24-hr rhythms in their environment. Daily fluctuations in stimuli/stressors of cardiac metabolism and oxidation-reduction (redox) status have been reported over the course of the day. It is therefore not surprising that the heart exhibits dramatic oscillations in various cellular processes over the course of the day, including transcription, translation, ion homeostasis, metabolism, and redox signaling. This temporal partitioning of cardiac processes is governed by a complex interplay between intracellular (e.g., circadian clocks) and extracellular (e.g., neurohumoral factors) influences, thus ensuring appropriate responses to daily stimuli/stresses. The purpose of the current article is to review knowledge regarding control of metabolism and redox biology in the heart over the course of the day, and to highlight whether disruption of these daily rhythms contribute towards cardiac dysfunction observed in various disease states.

Keywords: Chronobiology; Heart; Metabolism; Redox tone.

Figure1:. Time-of-day-dependent fluctuations in biventricular weight of the mouse heart.

A: Assimilated data from McGinnis et al and Brewer et al shows time-of-day-dependent fluctuations in biventricular weight (mg). B: Murine biventricular weight is 6.9% higher at the awake-to-sleep (dark-to-light; average of ventricles collected at ZT21, ZT24/0, and ZT3; n=28) transition compared to the sleep-to-awake (light-to-dark; average of ventricles collected at ZT9, ZT12, and ZT15; n=26) transition.

Figure 2:. Hypothetical mechanism for circadian control of redox tone in the heart, and increased susceptibility to cardiac dysfunction when disrupted.

A: Based on the current literature (as discussed in the text) we propose that decreased metabolic activity during sleep results in a higher resting mitochondrial membrane potential (ΔΨm). This condition is known to produce more ROS (superoxide/hydrogen peroxide), which we then propose controls redox signaling. In addition, through the modification of specific thiol groups on Keap1, Nrf2 is released to translocate to the nucleus. It can then initiate the transcriptional regulation of antioxidant enzymes which control levels of antioxidants such as glutathione (GSH) and HO-1, such that at the onset of increased metabolic demand, ROS are efficiently scavenged and do not damage contractile or metabolic proteins. Intrinsic circadian clocks likely optimize this system, through temporal regulation of both antioxidant and metabolic enzymes. This hypothesis suggests that the peak antioxidant levels in the circadian cycle will be at the sleep-to-awake transition. B: In pathological settings, increased oxidative stress, coupled with dysfunctional circadian clocks, suppress circadian control of the Keap1/Nrf2 system, leading to decreased levels of intracellular antioxidants. Oxidative protein modification and cardiac dysfunction then accumulates over time.

Figure 3.. The interplay between intrinsic (i.e., circadian clock) and neurohumoral factors in circadian control of both metabolism and redox tone.

In this scheme some of the key mechanisms influencing temporal control of cardiac metabolism and redox tone are summarized in the cardiomyocyte. Dashed lines depict metabolic pathways. Italics depicts examples of clock regulated genes. In this model, circadian-dependent transcriptional regulation in the nucleus (represented by the clock at an arbitrary time of day) controls the protein levels of key metabolic proteins (examples shown here are Pik3r1, phosphoinositide-3-kinase regulator subunit 1; Hk2, hexokinase 2 and Glut 4 Glut4, glucose transporter isoform 4; and Dgat2, diacylglycerol O-acyltransferase 2). This leads to changes in protein expression and substrate uptake/utilization, which in turn affects both mitochondria function and the hexose monophosphate pathway (HMP). A further level of regulation is provided by the impact of neurohumoral factors on glucose and fatty acid metabolism, as described in the text. The net effect is to integrate ATP (adenosine triphosphate) demand with metabolism, therefore meeting fluctuations in metabolic/energetic demands during the light/day cycle. The interface with redox signaling occurs at a number of levels, some of which involve the transcription factor Nrf2 (nuclear factor (erythroid-derived 2)-like 2). Increased levels of Nrf2 in the nucleus controls levels of glutathione (GSH) in the cell and the redox tone. Higher levels of GSH attenuate ROS (reactive oxygen species) signaling by changing the steady state levels of ROS signaling molecules such as H₂O_2, which can be generated by the mitochondria.