Epigenetic Regulation of Vascular Smooth Muscle Cell Function in Atherosclerosis

Abstract

Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling.

PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner

“…As illustrated in Fig. 4c, roflumilast treatment decreased dimethylation of histone H3-lysine 4 (H3K4me2), an activating histone mark induced by inflammatory stimulation [28], at the VCAM-1 promotor 12 h after TNF-α treatment. Next, we investigated the effect of Epac and PKA activation on histone H3-lysine 4 dimethylation at the VCAM-1 promoter.…”

“…Furthermore, roflumilast treatment had no effect on NF-κB translocation as well as VCAM-1 promoter activity, suggesting the involvement of regulatory components beyond the repression of transcription factor-dependent transactivation. As histone modifications control the accessibility of a transcription factor to a gene, they constitute a hierarchic upper-level of transcriptional control regulating gene expression in a specific manner [28]. Particularly methylation of H3K4 has been described as an activating histone mark that is highly enriched at the transcriptional start site (TSS) of active genes and induced following inflammatory stimulation [48,49].…”

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

“…On the other hand, several studies suggested that DNA methylation might participate in regulating VSMC phenotype and vascular remodeling. 24 Liu et al 25 reported a significant reduction in Tet2 expression in the neointima or coronary atherosclerotic plaques. Loss of Tet2 suppressed 5-hmC enrichment and affected the expression of VSMC differentiation marker genes, which in turn aggravated vascular remodeling.…”

“…Given that Tet2 was the predominant DNA demethylation enzyme in arteries, 24 we firstly investigated the expression of Tet2 among 3 groups. Using our panel of mouse aorta samples, we tested the abundance of RNA transcripts and protein.…”

“…In keeping with the changes of DNMT activity, 5-mC content was significantly increased in vehicle-treated ApoE −/− mice but declined close to normal level when treated with 5-aza ( Figure 2H). Collectively, these results suggested that the effect of 5-aza on DNA demethylation of the aorta containing atherosclerostic plaques was mediated via suppression of DNMT enzyme activity.Given that Tet2 was the predominant DNA demethylation enzyme in arteries, 24 we firstly investigated the expression of Tet2 among 3 groups. Using our panel of mouse aorta samples, we tested the abundance of RNA transcripts and protein.…”