Circadian System
Ana Beatriz Rezende Paula, ... Mauro César Isoldi, in Advances in Protein Chemistry and Structural Biology, 2023
3 Light as a modulator of cardiac protein expression
Much is known about the synchronization of internal rhythms with the light/dark cycle and the effect of different wavelengths, intensities, and timing of light on human physiology and behavior. A lot of research involving the environmental light track has been carried out under controlled laboratory conditions. Since the circadian clock evolved under natural conditions long before artificial light existed, research has been conducted today on the effects and impacts of daylight on the physiology of living things, despite the unpredictable and less controllable variations of environmental light (Danilenko, Wirz-Justice, Kräuchi, Weber, & Terman, 2000; Webler, Spitschan, Foster, Andersen, & Peirson, 2019).
Light is a crucial environmental cue for vision and for the entrainment of the central clock in the suprachiasmatic nucleus, mediated by melanopsin which is found localized in the intrinsically photosensitive ganglion cells of the retina (Aranda & Schmidt, 2021). Several physiological processes are modulated by light, such as sleep, alertness, pupil size and synchronization of circadian rhythms (Beier, Zhang, Yurgel, & Hattar, 2021).
Alterations in circadian rhythms arising from jet lag or shift work, can lead to damage of central oscillators (Witte et al., 1998) and impairment in the drag of internal clocks with the LD cycle, due to internal desynchronization between the central clock and peripheral oscillators (Molcan, Vesela, & Zeman, 2016). Such damage caused by these events and/or conditions is associated with the development of various disorders, such as cardiovascular disease (Khan, Duan, Yao, & Hou, 2018). Furthermore, recent studies have pointed to the impacts of artificial light on circadian rhythms. Normotensive and hypertensive rats exposed to artificial light for five weeks showed changes in protein expression in the left ventricle of the heart, in addition to reduced expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2), endothelin 1 (ET-1), and the angiotensin II type 1 receptor (Ag-II), important regulators of cardiac contraction (Sutovska, Miklovic, & Molcan, 2021). Heart rate and contractility of the heart are modulated via the autonomic nervous system, through the SERCA2 protein. This protein is involved in the regulation of cytoplasmic calcium by pumping calcium from the cytosol to the sarcoplasmic reticulum (Bovo, Huke, Blatter, & Zima, 2017). Its regulation occurs by phospholamban phosphorylation through stimulation of protein kinases A and C which is triggered by catecholamines, angiotensin 2 and ET-1, thus modulating cardiac activity (Okumura et al., 2014). In contrast, the return of calcium to the cytosol occurs through the ryanodine receptor 2 (Bovo et al., 2017). In short, artificial light would be activates the SCN, in the dark phase, and suppressing the activity of the autonomic nervous system and adrenal glands, leading to reduced calcium loading of the heart (Kalsbeek et al., 2012; Molcan et al., 2019).
Many cardiovascular parameters oscillate during the 24-hours period, such as metabolism, heart rate, cardiac output, and the synthesis and release of hormones (Durgan et al., 2005). Some cardiovascular events, such as acute myocardial infarction, ventricular tachyarrhythmias, and ruptured aortic aneurysms, are also influenced by circadian machinery, peaking in the morning (Cohen, Rohtla, Lavery, Muller, & Mittleman, 1997; Eksik et al., 2007; Manfredini et al., 2004). Rotter et al. (2014) sought to test whether calcineurin and the cardioprotective protein regulator calcineurin 1 (RCAN1), contribute to the circadian rhythm by protecting against cardiac damage from ischemia and reperfusion. WT mice, nocautes for Rcan1 (Rcan1-KO) and overexpressed for Rcan1 (Rcan1-Tg) were subjected to myocardial ischemia in a light-on condition between 10 am and 10 pm (AM) or between midnight and noon (PM). Surgeries occurred within the first two hours (AM) or the last two hours (PM) of the light phase. A ligature was performed on the left descending coronary (LAD) resulting in an ischemia, encompassing 60% of the left ventricle (LV). After 45 minutes of ischemia, the ligature was removed and reperfusion was confirmed. Western blotting reported that protein levels of the RCAN1.4 isoform were higher in ZT1 compared to ZT11. However, protein levels of RCAN1.1 and the catalytic subunit of calcineurin did not differ between ZTs. After 3 hours of infarction and reperfusion, the protein levels of RCAN1.4 increased regardless of the light exposure period (AM and PM). That is, the calcineurin/Rcan1.4 feedback loop is activated in response to I/R, regardless of the time of day when the challenge occurs. Even 24 hours after infarction, protein levels of RCAN1.4 remained elevated. Importantly, calceurin is a protein involved in synaptic signaling, neuron survival, cytokine production, and angiogenesis processes that contribute to myocardial survival after an episode of infarction.
Worthy of note, it is important to point out that circadian variations occur at both the physiological and molecular levels of the heart (Martino et al., 2004). At the transcriptional level, the mRNA profile exhibits rhythms throughout the LD cycle. These oscillations are essential for coordinating biological and biochemical processes in cardiac physiology. However, proteins are fundamentally important in the underlying processes. However, gene and protein expression levels do not always correlate, due to post-translational mechanisms (Nickel & Rabouille, 2009). It is estimated that about 7.8% of the soluble cardiac proteome varies over 24-hour cycles. Of these 90 spots (7.8%), 38 exhibit higher abundance in the light period (sleep time of mice), and 52 predominate in the dark period (wake time of mice). Among the various proteins present in the heart, noteworthy the trifunctional enzyme-β subunit, mitochondrial (HADHB), δ-1-pyrrolinie-5-carboxylate dehydrogenase, mitochondrial (P5CDh), aconitate hydratase, mitochondrial (ACO2), protein kinase CAMP-activated catalytic subunit α (PRKACA), ATP synthase-α, mitochondrial (ATP5A1), stress-induced phosphoprotein-1 (STIP1), peroxiredoxin-1 (PRDX1), insulin-like growth factor II (IGF2), inner membrane protein, mitochondrial (IMMT), and heat shock protein family D member 1 (HSPD1) (Podobed et al., 2014). Podobed et al. (2014), seeking to understand the relationship between the circadian clock and protein expression, evaluated the cardiac proteome in a CCM mouse model. They observed alterations in temporal expression profiles, with the most prominent proteins in the hearts of CCM animals being pyruvate dehydrogenase E1a, mitochondrial (PDHE1a), aspartate aminotransferase, mitochondrial (GOT2) and dihydrolipoamide S-succinyltransferase (DLST), while proteins of lower expression were P dehydrogenase, mitochondrial (ALDH2), lactate dehydrogenase B (LDHB), enoyl CoA hydratase, mitochondrial (ECHS1) and hydroxybutyrate dehydrogenase, mitochondrial (BDH1). Regulation of PDHE1a and LDHB occurrs at the translational level contributing to the observed rhythms in glucose and lactate metabolism and is supported by previous observations that rhythmic cardiac glucose and lactate metabolism are disrupted in CCM mice (Durgan, Pat, et al., 2011). Furthermore, the post-translational modification of the PDH protein in CCM hearts is potentially phosphorylation. PDH, when phosphorylated, is inactivated. Decreased PDH activity, in addition to decreased LDHB, ECHS1, and BDH1, may limit the acetyl-CoA production in CCM hearts. In other words, part of the cardiac proteome is regulated by the circadian clock, both modulating total protein levels and post-translational modifications (Podobed et al., 2014).
Studies have pointed to the effects of an altered LD cycle on cardiovascular physiology (Martino et al., 2007) and in the expression of cardiac molecules (Martino & Sole, 2009). Seeking to understand the effects of altered LD cycling on cardiovascular health and the cardiac proteome, WT animals were subjected to an established LD disruption protocol (10:10 L/D). Altered protein profiles of ALDH4A1, STIP1, IGF2, PER2 proteins and implications for cardiac function were identified. These findings highlight for the effects of circadian disruption, such as shift work, on cardiovascular health (Podobed et al., 2014).
In summary, these findings highlight for the effects of LD cycle manipulation on cardiac proteomics, which differs, quantitatively, within the 24 hours cycle (LD cycle). Variations in protein expression in the heart as well as cardiac function are dependent on the circadian clock mechanism of cardiomyocytes (Fig. 2). Therefore, further studies are needed for a better understanding of cardiovascular physiology and its disorders.