**2. Circadian rhythm**

Circadian rhythm is controlled by a molecular clock located in almost every cell. A hierarchical system organizes molecular clocks—the master clock is located in the suprachiasmatic nucleus (SCN) in the hypothalamus [2, 7], while the peripheral clocks are located in each organ or cell. The central clock regulates physiological functions via the autonomic nervous system, humoral mediators, and other still unknown factors [7, 8]. In the maintenance and generation of circadian or biological rhythm in humans, a whole series of anatomical (suprachiasmatic nucleus), neurological (retinohypothalamic paths) and neuroendocrine (melatonin) systems are involved, indicating that the biology of the circadian rhythm of humans is similar to that of animals [9].

The master clock in the SCN consists of about 100,000 neurons in humans. It is the only molecular clock that receives light as an input signal from the retina. Internal clocks are synchronized with light depending on the time of day. SCN receives a direct light signal from the retina via the optic nerve from the photoreceptor called the intrinsically photoreceptive retinal ganglion cell (ipRGC), which expresses the circadian photopigment, melanopsin [10]. The signal is further transmitted to peripheral clocks via the endocrine system [11, 12]. The central clock synchronizes each of the peripheral clocks in the body, and the primary circadian hormone is melatonin [13]. The pineal gland secretes melatonin during the night. Melatonin plays an essential role in maintaining the circadian rhythm depending on the period of light or darkness. The main difference between the master and peripheral clocks is in their degree of intercellular interaction. Peripheral clocks are under the influence of the master clock from the SCN via hormones, chemical signals and other metabolites (such as food), as well as by changes in the body, such as body temperature [11, 12].

On the other hand, due to the high degree of neuron connection the master clock in the SCN is not under the influence of internal signals but only under the influence of light [14]. Peripheral tissues integrate central clock signals with environmental factors (including sleepiness, physical activity, and feeding) and their autonomic rhythms which regulate the metabolism in a circadian manner [10]. The rhythm of the peripheral clocks in humans is measured by direct measurement of physiological changes, or by determining the expression of the clock genes. Central and peripheral clocks together control the daily circadian rhythm of the metabolism [15].

Feeding time is one of the key triggers or external factors that sets the phases of the peripheral clocks [15]. Complex feedback loops connect the circadian clock with metabolic pathways and integrate these systems independently of light [10]. It is believed that the central clock regulates the metabolism by hormones (primarily cortisol and melatonin) and synaptic signaling (via the autonomic nervous system) [10]. Feeding is a circadian event that serves not only as the output of the central clock, but also as an input signal for peripheral clocks because peripheral tissues communicate with the brain through ghrelin, leptin, glucose, and insulin. Circadian feeding contributes to the interworking of the clock and metabolism, which is crucial for metabolic homeostasis [16]. The central clock rhythm is primarily related to light, whereas peripheral tissue rhythms derive from the input of signals from the central clock, external factors (light, physical activity, feeding, and sleepiness) and the availability of numerous metabolites [15]. All these signals affect the molecular clock, creating a complex correlation between the circadian clock and physiological processes [10]. SCN coordinates all cellular circadian clocks in the organs and tissues through its rhythmic outcomes, to adapt physiology to Earth's rotation [17].

**23**

*Myocardial Infarction and Circadian Rhythm DOI: http://dx.doi.org/10.5772/intechopen.83393*

the risk of developing metabolic diseases [15].

**3. Molecular basis of circadian rhythm**

clock-controlled genes [23, 24].

ing an increased incidence of cardiovascular disease [18].

The two clock systems become desynchronized when their drivers or stimuli do not coincide because different stimuli affect the phases of the central and peripheral clocks. This mismatch disrupts the metabolism because the two clock systems coordinate interlinked metabolic pathways. Circadian rhythm mismatch increases

The central clock is primarily triggered by light, and its rhythm is often measured by determining the concentrations of melatonin, cortisol or body temperature [15]. The expression of the clock genes is disrupted in pathological conditions. Such a change may result in different tissue response to external signals and accelerate tissue damage. The loss of synchronization can lead to various diseases, includ-

The central clock genes are expressed in a circadian manner in the SCN, and light is one of the main initiators (so-called *zeitgeber*) and can reset the phase of the rhythm. The first circadian rhythm gene discovered was the *Per* gene in the fruit fly in 1971 [19, 20], while the first circadian rhythm gene discovered in the vertebrae was the *CLOCK* gene [21]. There are about 10 circadian rhythm genes known to regulate cyclic expression of mRNA and protein, via transcription and translation feedback loops [22]. In the SCN there are four essential proteins: ARNTL (Aryl Hydrocarbon Receptor Nuclear Translocator-Like) and CLOCK (Circadian Locomotor Output Cycles Caps) are activators, while PER (Period) and CRY (Cryptochrome) are transcription inhibitors. The feedback of the circadian rhythm gene maintains circadian oscillations in one cell at the transcriptional and posttranscriptional levels, and the transition from light to dark triggers these oscillations. The whole process of activation and repression of gene expression within the loop lasts for about 24 hours. These transcriptional factors trigger numerous physiological changes by acting on the expression of the same genes, and other

ARNTL and CLOCK heterodimers bind to regulatory elements of the promoters and enhancers (E-box) of the *PER* and *CRY* genes and stimulate their expression and the expression of other clock-controlled genes. Overnight the amount of PER and CRY proteins gradually increases, and heterodimers are created in the cytoplasm. The phosphorylated PER-CRY heterodimers are translocated into the nucleus where they inhibit the ARNTL-CLOCK protein complex. Therefore, during the day, transcription of *PER* and *CRY* genes is reduced, while the levels of PER and CRY protein decrease due to their degradation by ubiquitin. The PER-CRY heterodimers directly bind to the ARNTL-CLOCK complex, and as PER2 contains histone deacetylase, the chromatin structure changes, resulting in transcription termination. Also, the PER-CRY heterodimer is in interaction with RNA-binding proteins and helicase that are important in stopping transcription independently of the interaction with the ARNTL-CLOCK complex. Additionally, PER-CRY heterodimers regulate the transcription of various nucleic hormone receptors [25–28]. During the day a new cycle begins by the termination of the ARNTL-CLOCK heterodimer inhibition. Casein kinase 1 (CK1) controls the amount of phosphorylation or degradation of PER-CRY heterodimers and thereby determines the amount of PER-CRY heterodimer entering the nucleus and inhibiting the ARNTL-CLOCK complex. CK1 phosphorylates the proteins and thus regulates their activity [29]. The additional negative loop is REV-ERBα that binds to the REV-ERB/ROR response element (RRE) of the *ARNTL* and *CLOCK* genes, and prevents their transcription. Also, RORα (Retinoic Acid Receptor-related Orphan Receptor) binds

*Myocardial Infarction and Circadian Rhythm DOI: http://dx.doi.org/10.5772/intechopen.83393*

*Visions of Cardiomyocyte - Fundamental Concepts of Heart Life and Disease*

Circadian rhythm is controlled by a molecular clock located in almost every cell. A hierarchical system organizes molecular clocks—the master clock is located in the suprachiasmatic nucleus (SCN) in the hypothalamus [2, 7], while the peripheral clocks are located in each organ or cell. The central clock regulates physiological functions via the autonomic nervous system, humoral mediators, and other still unknown factors [7, 8]. In the maintenance and generation of circadian or biological rhythm in humans, a whole series of anatomical (suprachiasmatic nucleus), neurological (retinohypothalamic paths) and neuroendocrine (melatonin) systems are involved, indicating that the biology of the circadian rhythm of humans is

The master clock in the SCN consists of about 100,000 neurons in humans. It is the only molecular clock that receives light as an input signal from the retina. Internal clocks are synchronized with light depending on the time of day. SCN receives a direct light signal from the retina via the optic nerve from the photoreceptor called the intrinsically photoreceptive retinal ganglion cell (ipRGC), which expresses the circadian photopigment, melanopsin [10]. The signal is further transmitted to peripheral clocks via the endocrine system [11, 12]. The central clock synchronizes each of the peripheral clocks in the body, and the primary circadian hormone is melatonin [13]. The pineal gland secretes melatonin during the night. Melatonin plays an essential role in maintaining the circadian rhythm depending on the period of light or darkness. The main difference between the master and peripheral clocks is in their degree of intercellular interaction. Peripheral clocks are under the influence of the master clock from the SCN via hormones, chemical signals and other metabolites (such as food), as well as by changes in the body, such

On the other hand, due to the high degree of neuron connection the master clock in the SCN is not under the influence of internal signals but only under the influence of light [14]. Peripheral tissues integrate central clock signals with environmental factors (including sleepiness, physical activity, and feeding) and their autonomic rhythms which regulate the metabolism in a circadian manner [10]. The rhythm of the peripheral clocks in humans is measured by direct measurement of physiological changes, or by determining the expression of the clock genes. Central and peripheral clocks together control the daily circadian rhythm of

Feeding time is one of the key triggers or external factors that sets the phases of the peripheral clocks [15]. Complex feedback loops connect the circadian clock with metabolic pathways and integrate these systems independently of light [10]. It is believed that the central clock regulates the metabolism by hormones (primarily cortisol and melatonin) and synaptic signaling (via the autonomic nervous system) [10]. Feeding is a circadian event that serves not only as the output of the central clock, but also as an input signal for peripheral clocks because peripheral tissues communicate with the brain through ghrelin, leptin, glucose, and insulin. Circadian feeding contributes to the interworking of the clock and metabolism, which is crucial for metabolic homeostasis [16]. The central clock rhythm is primarily related to light, whereas peripheral tissue rhythms derive from the input of signals from the central clock, external factors (light, physical activity, feeding, and sleepiness) and the availability of numerous metabolites [15]. All these signals affect the molecular clock, creating a complex correlation between the circadian clock and physiological processes [10]. SCN coordinates all cellular circadian clocks in the organs and tissues through its rhythmic outcomes, to adapt physiology to

**2. Circadian rhythm**

similar to that of animals [9].

as body temperature [11, 12].

the metabolism [15].

Earth's rotation [17].

**22**

The two clock systems become desynchronized when their drivers or stimuli do not coincide because different stimuli affect the phases of the central and peripheral clocks. This mismatch disrupts the metabolism because the two clock systems coordinate interlinked metabolic pathways. Circadian rhythm mismatch increases the risk of developing metabolic diseases [15].

The central clock is primarily triggered by light, and its rhythm is often measured by determining the concentrations of melatonin, cortisol or body temperature [15]. The expression of the clock genes is disrupted in pathological conditions. Such a change may result in different tissue response to external signals and accelerate tissue damage. The loss of synchronization can lead to various diseases, including an increased incidence of cardiovascular disease [18].
