Cell‑specific histone modifications in atherosclerosis (Review)

Abstract

Histone modifications are the key epigenetic mechanisms that have been identified to regulate gene expression in many human diseases. However, in the early developmental stages, such as in utero and the postnatal stages, histone modifications are essential for gene regulation and cell growth. Atherosclerosis represents a classical example of the involvement of different cell types, and their cumulative effects in the development of atheroma and the progression of the disease. Post translational modifications on proteins either induces their functional activity or renders them inactive. Post translational modifications such as methylation or acetylation on histones have been well characterized, and their role in enhancing or inhibiting specific gene expression was clearly elucidated. In the present review article, the critical roles of different histone modifications that occur in atherosclerosis have been summarized. Different histone proteins have been identified to serve a critical role in the development of atherosclerosis. Specifically, histone methylation and histone acetylation in monocytes, macrophages, vascular smooth muscle cells and in endothelial cells during the progression of atherosclerosis, have been well reported. In recent years, different target molecules and genes that regulate histone modifications have been examined for their effects in the treatment of atherosclerosis in animal models and in clinical trials. An increasing body of evidence suggests that these epigenetic changes resulting from DNA methylation and non-coding RNA may also be associated with histone modifications, thereby indicating that novel therapeutic strategies can be developed by targeting these post translational modifications, which may in turn aid in the treatment of atherosclerosis.

Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect

“…ABCG1 has been reported to be regulated by HDAC9-mediated changes in acetylation (20,21) and may be targeted by the HDAC9 epigenetic alteration. We confirmed that ABCG1 protein expression is indeed down-regulated in response to mevastatin and atorvastatin treatment (Figure 2d).…”

“…HDAC9 -deficient macrophages and monocytes directly increased the accumulation of total acetylated H3 and H3K9 at the promoter of the ABCG1 gene (20,21), thereby inducing the transcription of the ABCG1 gene, indicating that HDAC9 mediates the expression of ABCG1 through promoter-mediated acetylation. This is of particular interest, as several studies have reported a role of ABCG1 in obesity, insulin resistance and T2D.…”

Epigenetic Regulation of Endothelial Cell Function by Nucleic Acid Methylation in Cardiac Homeostasis and Disease

“…It is now appreciated that m6A methylation regulates structural and functional properties of RNA and that this modification is essential for maintenance of cellular homeostasis. Indeed, various studies have highlighted a critical role for m6A methylation in key biological processes such as embryonic and tissue development [124,125], control of circadian clock [126], regulation of body weight and metabolism [127,128], learning and memory [129], spermatogenesis [111,113], response to stress [130,131] and cellular renewal and differentiation [132][133][134]. It is therefore unsurprising that dysfunctional changes in this RNA modification are associated with pathological conditions, including various cancers [135], obesity and metabolic diseases [136], neurological disorders [137] and cardiovascular diseases, such as arrhythmia [138], coronary artery disease [136] and HF [14,139,140].…”

Potential epigenetic therapeutics for atherosclerosis treatment

“…Histone modifications include methylation, acetylation, phosphorylation, ubiquitination, sumoylation and glycosylation which are collectively referred to as histone post-translational modifications (PTMs) [40]. Among these modifications, Histone acetylation and methylation are the most studied modifications in the context of inflammation and cardiovascular disease [41].…”