**3. Molecular basis of circadian rhythm**

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 clock-controlled genes [23, 24].

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 to the same regulatory elements of the *ARNTL* gene as well as REV-ERBα. With REV-ERBα degradation overnight, RORα promotes transcription of the *ARNTL* gene [30]. The second regulatory loop consists of ARNTL-CLOCK heterodimers which promote the transcription of the nucleic receptors REV-ERBα and RORα [31] (**Figure 1**).

Circadian clock genes have an essential role in many physiological processes. Thus, animal models demonstrate that the *ARNTL* gene plays an essential role in lipid metabolism because it induces the expression of genes involved in lipogenesis in adipose tissue in a circadian manner [32]. Pancreatic beta cells have a circadian clock dependent on ARNTL and CLOCK protein oscillations, which regulate insulin secretion depending on the stage of alertness. Abnormalities of the pancreas clock may trigger the onset of diabetes [33]. It was found that *CLOCK* polymorphisms are associated with body weight, the risk for metabolic syndrome and insomnia in humans [9, 32], and polymorphisms of the *PER2* and *PER3* genes are associated with sleep disorders [34, 35]. Some variants of *CRY1* and *CRY2* genes are associated with metabolic syndrome, particularly hypertension and increased triglyceride levels in the blood [36]. Many variants of the circadian rhythm genes are associated with the risk factors for the development of cardiovascular diseases such as blood pressure, glucose concentration [23, 37]. An overview of the essential circadian rhythm genes with their roles is shown in **Table 1** [38, 39].

#### **Figure 1.**

*The molecular mechanism of circadian rhythm in humans. ARNTL and CLOCK activate transcription of CRY and PER, nuclear receptors (REV-ERBα and RORα) and other clock-controlled genes. CRY and PER heterodimerize and phosphorylate by casein kinases and translate into the nucleus where they prevent binding of the ARNTL-CLOCK to the regulatory regions of target genes. In the second feedback loop, REV-ERBα prevents the transcription of ARNTL because it binds to the RRE element, while overnight the same regulatory elements bind RORα and activate transcription of ARNTL. Also, ARNT-CLOCK heterodimers activate transcription of the REV-ERBα and RORα proteins. ARNTL—aryl hydrocarbon receptor nuclear translocator-like, CLOCK—circadian locomotor output cycles kaput, CRY—cryptochrome, PER—period, P—phosphate, RORα—retinoic-related orphan receptor alpha, RRE element—REV-ERB/ROR response element, Ub—ubiquitin.*

**25**

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

**Gene Function**

*ARNTL* (*Aryl hydrocarbon Receptor Nuclear Translocator-Like*)

*CLOCK* (*Circadian Locomotor Output Cycles Kaput*)

*CRY1* (*Cryptochrome 1*) *CRY2* (*Cryptochrome 2*)

*REV-ERBα (nuclear receptor subfamily 1 group D member 1)*

*RORα* (*Retinoic-related orphan* 

*PER1* (*Period 1*) *PER2* (*Period 2*) *PER3* (*Period 3*)

*receptor alpha*)

**Table 1.**

cardiovascular diseases [15, 40, 41].

*The essential circadian rhythm genes in mammals.*

overtaking mortality rates for infectious diseases [44].

of these contribute to total cardiovascular risk [45].

**4. Cardiovascular diseases**

Numerous studies on animal models, as well as human populations, have confirmed the association of the circadian clock gene with metabolic syndrome and

Rhythmically expressed. Physically associates with CLOCK. Promotes transcription of *PER* and *CRY*. It is involved in the risk for hypertension,

Constitutively expressed. Physically associates with *ARNTL*. Promotes transcription of *PER* and *CRY*. It is involved in the platelet rhythmic activity, response of cardiomyocytes to fatty acids, lipid, and glucose

Physically associates with and stabilizes PER. Negative regulator of Per

Physically associates with CRY. Positive regulator of *ARNTL.* They are

Associates with regulatory elements and negative regulator of the *ARNTL* and *CLOCK* transcription. It is involved in triglyceride and lipid

Associates with regulatory elements and positive regulator of the

adipogenesis, and glucose metabolism. *CK1*ε (*Casein kinase 1 ε*) Physically associates with and phosphorylates PER. Affects PER stability

involved in the aortic endothelial function.

metabolism, and circadian activity of PAI-1.

*ARNTL.* It is involved in lipid metabolism. *TIM* (*Timeless*) Circadian function not known. Physically associates with CRY. Negative

regulator of *PER* and *CRY* transcription *in vitro*.

and nuclear localization.

and Cry transcription.

metabolism.

The WHO data for 2017 show that cardiovascular diseases were the cause of 19.9 million deaths worldwide, and about 80% of deaths from cardiovascular diseases were due to myocardial infarction and stroke [42]. It is estimated that by 2030, 23.6 million people will die annually due to cardiovascular diseases [43]. Cardiovascular diseases are the primary cause of death in developed countries of the world, and in less developed parts of the world, this mortality is rising and

There are variable and constant risk factors for cardiovascular disease. The variable risk factors are those that can be affected by therapy and lifestyle change, such as smoking, hyperlipoproteinemia, hypertension, and to some extent diabetes and homocysteinemia. The constant risk factors cannot be affected, namely age, genetic predisposition, gender, and menopause. The general risk factors which can be altered most are smoking, hypertension and hyperlipidemia, and obesity and diabetes whose prevalence has risen in the last few decades. However, some recent risk factors (fibrinogen, lipoprotein (a), homocysteine) should not be ignored. All

Cardiometabolic risk factors are determined by a cluster of metabolic and cardiovascular changes. Diabetes and obesity are also associated with reduced quality of life and increased economic burden on the person and society [46, 47]. Cardiovascular diseases and type 2 diabetes share common pathophysiological


**Table 1.**

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

rhythm genes with their roles is shown in **Table 1** [38, 39].

(**Figure 1**).

to the same regulatory elements of the *ARNTL* gene as well as REV-ERBα. With REV-ERBα degradation overnight, RORα promotes transcription of the *ARNTL* gene [30]. The second regulatory loop consists of ARNTL-CLOCK heterodimers which promote the transcription of the nucleic receptors REV-ERBα and RORα [31]

Circadian clock genes have an essential role in many physiological processes. Thus, animal models demonstrate that the *ARNTL* gene plays an essential role in lipid metabolism because it induces the expression of genes involved in lipogenesis in adipose tissue in a circadian manner [32]. Pancreatic beta cells have a circadian clock dependent on ARNTL and CLOCK protein oscillations, which regulate insulin secretion depending on the stage of alertness. Abnormalities of the pancreas clock may trigger the onset of diabetes [33]. It was found that *CLOCK* polymorphisms are associated with body weight, the risk for metabolic syndrome and insomnia in humans [9, 32], and polymorphisms of the *PER2* and *PER3* genes are associated with sleep disorders [34, 35]. Some variants of *CRY1* and *CRY2* genes are associated with metabolic syndrome, particularly hypertension and increased triglyceride levels in the blood [36]. Many variants of the circadian rhythm genes are associated with the risk factors for the development of cardiovascular diseases such as blood pressure, glucose concentration [23, 37]. An overview of the essential circadian

*The molecular mechanism of circadian rhythm in humans. ARNTL and CLOCK activate transcription of CRY and PER, nuclear receptors (REV-ERBα and RORα) and other clock-controlled genes. CRY and PER heterodimerize and phosphorylate by casein kinases and translate into the nucleus where they prevent binding of the ARNTL-CLOCK to the regulatory regions of target genes. In the second feedback loop, REV-ERBα prevents the transcription of ARNTL because it binds to the RRE element, while overnight the same regulatory elements bind RORα and activate transcription of ARNTL. Also, ARNT-CLOCK heterodimers activate transcription of the REV-ERBα and RORα proteins. ARNTL—aryl hydrocarbon receptor nuclear translocator-like, CLOCK—circadian locomotor output cycles kaput, CRY—cryptochrome, PER—period, P—phosphate, RORα—retinoic-related orphan receptor alpha, RRE element—REV-ERB/ROR response* 

**24**

*element, Ub—ubiquitin.*

**Figure 1.**

*The essential circadian rhythm genes in mammals.*

Numerous studies on animal models, as well as human populations, have confirmed the association of the circadian clock gene with metabolic syndrome and cardiovascular diseases [15, 40, 41].

### **4. Cardiovascular diseases**

The WHO data for 2017 show that cardiovascular diseases were the cause of 19.9 million deaths worldwide, and about 80% of deaths from cardiovascular diseases were due to myocardial infarction and stroke [42]. It is estimated that by 2030, 23.6 million people will die annually due to cardiovascular diseases [43].

Cardiovascular diseases are the primary cause of death in developed countries of the world, and in less developed parts of the world, this mortality is rising and overtaking mortality rates for infectious diseases [44].

There are variable and constant risk factors for cardiovascular disease. The variable risk factors are those that can be affected by therapy and lifestyle change, such as smoking, hyperlipoproteinemia, hypertension, and to some extent diabetes and homocysteinemia. The constant risk factors cannot be affected, namely age, genetic predisposition, gender, and menopause. The general risk factors which can be altered most are smoking, hypertension and hyperlipidemia, and obesity and diabetes whose prevalence has risen in the last few decades. However, some recent risk factors (fibrinogen, lipoprotein (a), homocysteine) should not be ignored. All of these contribute to total cardiovascular risk [45].

Cardiometabolic risk factors are determined by a cluster of metabolic and cardiovascular changes. Diabetes and obesity are also associated with reduced quality of life and increased economic burden on the person and society [46, 47]. Cardiovascular diseases and type 2 diabetes share common pathophysiological

mechanisms of insulin resistance and risk factors for cardiovascular diseases, such as metabolic syndrome. Excessive weight plays a significant role because fatty tissue becomes an active endocrine organ that secretes low-level inflammation mediators, and these stimulate the development of metabolic syndrome and vascular diseases [32, 48, 49].
