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DNA methylation processes in atherosclerotic plaque

  • Einari Aavik
    Affiliations
    Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O.Box 1627 (Neulaniementie 2), FIN-70211, Kuopio, Finland
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  • Mohan Babu
    Affiliations
    Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O.Box 1627 (Neulaniementie 2), FIN-70211, Kuopio, Finland
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  • Seppo Ylä-Herttuala
    Correspondence
    Corresponding author. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O.Box 1627 (Neulaniementie 2), FIN-70211, Kuopio, Finland.
    Affiliations
    Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O.Box 1627 (Neulaniementie 2), FIN-70211, Kuopio, Finland

    Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
    Search for articles by this author

      Abstract

      Underlying mechanisms of cardiovascular diseases (CVD) have been investigated for over 100 years and novel molecular level mechanisms in the pathophysiology are still continuously being discovered. Genetic polymorphisms (SNPs = single nucleotide polymorphisms) have explained about one tenth of the CVD risk, but polymorphisms fail to account for gene-environment interactions i.e. explain the dynamics of epigenome modifications in CVD. Accumulating evidence suggests that epigenetic modifications are actively reshaping pathological processes (e.g. dedifferentiation of smooth muscle cells, accumulation of senescent cells) in CVD. Senescence of vascular cells in ageing arteries not only counteracts regenerative processes but also exacerbates atherogenesis. Epigenome modifications include changes in DNA methylation, histone code and expression of non-coding RNAs. DNA methylation is a major epigenetic regulator modulating cell-type specific gene expression in mural cells, but there is some controversy regarding how to interpret the role of DNA hyper- and hypomethylation in CVD pathology. DNA hypomethylation (loss of methyl cytosines) appears to predominate in atherosclerosis, while a few genes become more methylated (i.e. hypermethylated) as the disease progresses in medium-sized and large arteries. The actual time-course of atherosclerosis-linked changes in genomic DNA methylation is still poorly studied. This review highlights recent novel findings which link alterations in DNA methylation to atherogenesis and points out new potential approaches for novel treatments.

      Keywords

      Abbreviations:

      5 mC (5-methylcytosine), 5hmC (5-hydroxymethylcytosine), 5fmc (5-formylcytosine), 5caC (5-carboxylcytosine), BER (base-excision repair), BM (bone marrow), CGI (CpG island), CSE (cystathionine -γ-lyase), CHIP (clonal hematopoiesis of indeterminate potential), DNMT (DNA methyl transferase), H3K4me1 (histone 3 lysine 4 monomethylation), Hcy (homocysteine), HHcy (hyperhomocysteinemia), HSC (hematopoietic stem cell), HSPC (chematopoietic stem and progenitor cell), HDAC (histone deacetylase), HMT (histone methyl transferase), MBD (methyl cytosine binding domain), MPG (methylpurine DNA glycosylase), NuRD (nucleosome remodeling deacetylase), NZW (New Zealand White), SAH (S-adenosylhomocysteine), SAM (S-adenosylmethionine), SMC (smooth muscle cell), TDG (thymine-DNA-lycosylase), TET (ten-eleven translocation)
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