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Arterioscler Thromb Vasc Biol. 2017 Jan;37(1):84-97. doi: 10.1161/ATVBAHA.116.307923. Epub 2016 Nov 22.

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

Author information

1
From the Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (J.Z., H.L., K.W., Y.X., W.P.); Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China (P.L.); and Interdisciplinary Institute for Neuroscience, University of Bordeaux, France (P.Z.).
2
From the Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (J.Z., H.L., K.W., Y.X., W.P.); Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China (P.L.); and Interdisciplinary Institute for Neuroscience, University of Bordeaux, France (P.Z.). pwenhui@tongji.edu.cn xuyawei@tongji.edu.cn.

Abstract

OBJECTIVE:

DNA methylation plays an important role in chronic diseases such as atherosclerosis, yet the mechanisms are poorly understood. The objective of our study is to indicate the regulatory mechanisms of DNA methylation in vascular smooth muscle cells (VSMCs) and its roles in atherosclerosis.

APPROACH AND RESULTS:

In ApoE-/- mice fed a Western diet, DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, significantly attenuated atherosclerotic lesions (20.1±2.2% versus 30.8±7.5%; P=0.016) and suppressed DNA methyltransferase activity and concomitantly decreased global 5-methylcytosine content in atherosclerotic lesions of ApoE-/- mice. Using a carotid ligation model, we found that 5-aza-2'-deoxycytidine also dramatically inhibited neointimal formation (intimal area: 2.25±0.14×104 versus 4.07±0.22×104 μm2; P<0.01). Abnormal methylation status at the promoter of ten-eleven translocation 2, one of the key demethylation enzymes in mammals, was ameliorated after 5-aza-2'-deoxycytidine treatment, which in turn caused an increase in global DNA hydroxymethylation and 5-hydroxymethylcytosine enrichment at the promoter of Myocardin. In vitro, 5-aza-2'-deoxycytidine treatment or DNA methyltransferase 1 knockdown decreased global 5-methylcytosine content and restored Myocardin expression in VSMCs induced by platelet-derived growth factor, thus preventing excessive VSMCs dedifferentiation, proliferation, and migration. Furthermore, DNA methyltransferase 1 binds to ten-eleven translocation 2 promoter and is required for ten-eleven translocation 2 methylation in VSMCs.

CONCLUSIONS:

The inhibitory effects of DNA demethylation on global 5-methylcytosine content and ten-eleven translocation 2 hypermethylation in atherosclerotic aorta can recover 5-hydroxymethylcytosine enrichment at the Myocardin promoter and prevent VSMC dedifferentiation and vascular remodeling.

KEYWORDS:

DNA methylation; aorta; atherosclerosis; platelet-derived growth factor; vascular remodeling

PMID:
27879253
DOI:
10.1161/ATVBAHA.116.307923
[Indexed for MEDLINE]

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