Macrophage-mediated inflammatory responses occur throughout all stages of atherosclerosis. DNA methylation is one of the critical epigenetic mechanisms and is associated with the development of atherosclerosis. The underlying mechanism of epigenetic regulation of macrophage inflammation (M1 activation) remains unclear. Here we aim to study the role of DNA methyltransferase 1 (DNMT1) in modulating macrophage inflammation and atherosclerosis. DNMT1 expression is up-regulated in THP-1-derived macrophages upon treatment with lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). Overexpression of DNMT1 promotes the LPS- and IFN-γ-induced M1 activation whereas inhibition of DNMT1 attenuates it. Consistently, DNMT1 expression is elevated in macrophages in atherosclerotic plaques from human and mouse specimens; compared with the Dnmt1wild-type, myeloid Dnmt1 deficiency in mice in an Apolipoprotein E (ApoE) knockout background or receiving AAV-PSCK9 injection and carotid partial ligation results in ameliorated atheroma formation and suppressed plaque inflammation. The promoter regions of atheroprotective Krüppel-like factor 4 (KLF4) are hypermethylated in M1- activated macrophages. DNMT1 down-regulates the expression of KLF4, probably through catalyzing DNA methylation of the promoter regions of KLF4. Gain- and loss-of function study of KLF4 indicates that the DNMT1-mediated macrophage M1 activation is dependent on KLF4. Our data demonstrate a proatherogenic role for DNMT1 as a defining factor in macrophage inflammation both in vitro and in vivo. DNMT1 promotes macrophage M1 activation by suppressing KLF4 expression. Thus macrophage-specific DNMT1 inhibition may provide an attractive therapeutic potential to prevent or reduce atherosclerosis.
Keywords: Atherosclerosis; DNMT1; Inflammation; KLF4; Macrophage.
Copyright © 2019. Published by Elsevier Ltd.
Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages.J Biol Chem. 2005 Nov 18;280(46):38247-58. doi: 10.1074/jbc.M509378200. Epub 2005 Sep 16. J Biol Chem. 2005. PMID: 16169848
DNMT1-PPARγ pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice.Sci Rep. 2016 Aug 17;6:30053. doi: 10.1038/srep30053. Sci Rep. 2016. PMID: 27530451 Free PMC article.
Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis.PLoS One. 2016 Jun 13;11(6):e0157265. doi: 10.1371/journal.pone.0157265. eCollection 2016. PLoS One. 2016. PMID: 27295295 Free PMC article.
Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report.Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):2836-8. doi: 10.1161/ATVBAHA.112.300471. Epub 2012 Oct 11. Arterioscler Thromb Vasc Biol. 2012. PMID: 23065827 Free PMC article.
The role of epigenetics in the endothelial cell shear stress response and atherosclerosis.Int J Biochem Cell Biol. 2015 Oct;67:167-76. doi: 10.1016/j.biocel.2015.05.001. Epub 2015 May 13. Int J Biochem Cell Biol. 2015. PMID: 25979369 Free PMC article. Review.
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