Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 37, Issue 1, Pages 84-97Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.116.307923
Keywords
aorta; atherosclerosis; DNA methylation; platelet-derived growth factor; vascular remodeling
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Funding
- National Natural Science Foundation of China [81370391]
- Key Grant for Shanghai Science and Technology Foundation [14JC1401202]
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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+/-0.14x10(4) versus 4.07+/-0.22x10(4) mu m(2); 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.
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