**5. Histone modification and CVDs**

Post-translational modifications occur at amino acid residues in the amino-terminal regions of histone and cover histone acetylation, methylation, phosphorylation, sumoylation, and ubiquitination. It controls chromatin remodeling and gene expression [3, 23]. Histone acetylation is a sign of transcription activation [75], while histone methylation can both stimulate and inhibit transcription [28, 75]. Post-translational histone modifications control genes coding clock proteins [46, 75]. Epigenetic irregularities are related to different disorders, including atherosclerosis [4, 76].

Histone modifications occur at the CCG promoters in a circadian fashion [4, 44, 77, 78]. The core clock protein, CLOCK, has HAT activity. It revealed the molecular association among epigenetic mechanisms and circadian rhythm [4, 19, 59, 79]. CLOCK acetylates ARNTL, which facilitates CRY-dependent repression [19, 28], and interaction of CRY1 with the ARNTL-CLOCK heterodimer [9]. CLOCK and NPAS2 attract different HATs to the promoter of the *PER1* in vascular tissues [59, 78]. The rhythmic binding of ARNTL and CLOCK transcriptional activators directly influences the acetylation of specific histone lysine residues near the DNA-binding site without the involvement of additional HAT enzymes [59]. CLOCK acetylates additional nonhistone proteins that have crucial roles in the regulation of different cellular events [4].

SIRT1 is an NAD + -dependent histone deacetylase [4, 59, 80]. It is needed for rhythmic transcription of some clock genes, such as *ARNTL*, *CRY1*, and *PER2* [80, 81]. STIR1 represents the molecular connection between metabolic processes, chromatin remodeling, and circadian physiology [4]. SIRT1 plays a crucial role in metabolism. It deacetylates some proteins of the metabolic pathways and regulates gene expression by histone deacetylation [75]. *SIRT1* expression levels are nearly constant over 24 h, just like relatively constant *CLOCK* gene expression levels\*\*\* [4, 82–85]. The HAT function of CLOCK is balanced by SIRT1, which deacetylates H3 and ARNTL, and PER2 [79, 83, 86]. SIRT1 binds to ARNTL-CLOCK within a chromatin complex that, in a circadian fashion, binds to CCG promoters [4, 87]. ARNTL and PER2 are SIRT1 targets [4]. SIRT1 associates with ARNTL-CLOCK heterodimers and improves the deacetylation and degradation of PER2 [86]. SIRT1 deacetylates clock proteins in a circadian fashion [4]. HDAC3 is a deacetylase that modulates histone acetylation of circadian genes, especially those included in lipid

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].
