title: The Yin-Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling.
abstract: 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.
  
  
  
  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±0.14×104versus 4.07±0.22×104μm2; 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.
  
  
  
  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.
authors.affiliation: 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.).
authors.forename: Jianhui
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: 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.).
authors.forename: Peipei
authors.initials: P
authors.lastname: Luan
authors.affiliation: 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.).
authors.forename: Hailing
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 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.).
authors.forename: Wenhui
authors.initials: W
authors.lastname: Peng
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D054337:Cell Dedifferentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000077209:Decitabine; D059305:Diet, High-Fat; D049308:Dioxygenases; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects; D000099251:Myocardin
chemical_list: D044503:5-Methylcytosine; D001057:Apolipoproteins E; D001374:Azacitidine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D000077209:Decitabine; D049308:Dioxygenases; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099251:Myocardin; C011865:5-hydroxymethylcytosine; C551914:Tet2 protein, mouse
keywords: DNA methylation; aorta; atherosclerosis; platelet-derived growth factor; vascular remodeling