**7. Conclusion**

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

metabolism, such as REV-ERBα [88–92]. Mutations of circadian rhythm proteins that can either modify histones (such as CLOCK) or link to histone modifiers (such as ARNTL, PER2, and REV-ERBα) are related to metabolic syndrome [75, 79]. Endogenous SIRT1 plays a crucial role in mediating cell death/survival processes and is involved in the pathogenesis of the CVDs [28, 93]. The ARNTL sumoylation plays an essential role in ARNTL accumulation and circadian rhythmicity [86]. Histone modifications, and particularly HDACs, have a significant role in the control of vascular homeostasis. Dysregulation of HDAC could lead to the formation of atherosclerotic lesions [14, 94]. In human carotid arteries, histone methylation and acetylation present recognizable patterns depending on the seriousness of the plaque [46]. Inhibition of HDACs leads to reduced inflammation and atherogenesis [46, 95]. In animal studies, HDAC inhibitors reduce the size of MI and ischemia-reperfusion injury after revascularization [46, 96]. The inhibition of HDAC may improve myocardial recovery and block post-infarction remodeling [46]. Fibrosis after MI was reduced by valproic acid, an HDAC inhibitor [14, 97].

MicroRNAs (miRNAs) are small noncoding RNA molecules that repress the expression of target messenger RNAs [1, 3, 5, 98]. MicroRNA dysregulation is associated with cardiovascular diseases, lipid metabolism, endothelial function,

Oscillating microRNAs, based on external triggers, could affect the expression of target genes in a circadian fashion independently of clock genes [5, 99]. In plasma and serum of CVD patients are observed decreased levels of numerous miRNAs, such as miRNA-126, miRNA-17, miRNA-145, miRNA-92a, and miRNA-155 [3]. MiRNAs control the development of atherosclerosis through their action on endothelial function, plaque progression and rupture, and blood vessel development [46]. MiRNA-126 expressed by endothelial cells serves as an adverse adjuster of vascular inflammation, while miRNA-33 plays a vital role in inhibiting the critical genes implicated in cellular cholesterol export [14, 100]. Some miRNAs target DNMTs and thus regulate the level of DNA methylation in atherosclerotic lesions [14]. MiRNA-148 changes HDL and LDL cholesterol levels in murine models and

MiRNA-24, 29a, and 30a influence the circadian rhythm by regulating the stability and translation of PER1 and PER2 mRNAs [5]. The ARNTL-CLOCK heterodimer controls miRNA-142–3p and, in turn, can target ARNTL [5, 103, 104]. MiRNA-21 is a PER2-dependent miRNA and mediates PER2-obtained cardioprotection [5, 105]. Through cellular stress, PER2-dependent miRNA-21 controls cellular glycolysis. Myocardial ischemia causes activation of pathways aimed at increasing the efficiency of myocardial oxygen [5, 106]. Suppression of miRNA-21 reduces the

A valuable sign of myocardial cell death is the plasma levels of miRNA-208 [3, 107]. MiRNAs have a function in remodeling after MI, a mechanism closely associated with the expansion of tissue fibrosis [14]. A more sensitive biomarker of acute

MicroRNAs could potentially become new modulators of circadian rhythms and could have a positive effect on cardiovascular physiology [5]. MiRNAs regulate about 60% of all human genes [46]. Therapeutic strategies should target specific microRNAs and thus reduce their capacity to inhibit circadian rhythm components or circadian rhythm output genes [5, 108–112]. Administration of microRNAs in a circadian-dependent fashion could serve to adapt the impaired circadian system,

ventricular hypertrophy, and post-infarction dysrhythmias [1, 5].

thus has a vital function in lipid metabolism [46, 101, 102].

fibrotic response and enhances cardiac activity [5].

non-STEM MI is miRNA-499 than cardiac troponin T [46].

**42**

**6. MicroRNAs and CVDs**

The epigenetic variations of an individual change throughout a lifetime and epigenome profiles, instead of genotypes, are reflected in phenotypes in epigenetic epidemiological studies. Therefore, epigenetic modifications are the reason or a result of a pathological condition. Understanding the epigenetic contribution to CVD pathology may help to develop new treatments and diagnostic approaches. Epigenetic biomarkers might be very useful in treatment monitoring and predicting disease outcome. Epigenetic events can potentially be reversibly altered depending on environmental and nutritional factors. Understanding epigenetic mechanisms may identify valuable, novel biomarkers for disease.
