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

DOI Web Site 被引用文献1件
  • Jianhui Zhuang
    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.).
  • Peipei Luan
    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.).
  • Hailing Li
    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.).
  • Kai Wang
    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.).
  • Pei Zhang
    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.).
  • Yawei Xu
    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.).
  • Wenhui Peng
    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.).

説明

<jats:sec> <jats:title>Objective—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> In ApoE <jats:sup>−/−</jats:sup> 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%; <jats:italic>P</jats:italic> =0.016) and suppressed DNA methyltransferase activity and concomitantly decreased global 5-methylcytosine content in atherosclerotic lesions of ApoE <jats:sup>−/−</jats:sup> mice. Using a carotid ligation model, we found that 5-aza-2′-deoxycytidine also dramatically inhibited neointimal formation (intimal area: 2.25±0.14×10 <jats:sup>4</jats:sup> versus 4.07±0.22×10 <jats:sup>4</jats:sup> μm <jats:sup>2</jats:sup> ; <jats:italic>P</jats:italic> <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. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec>

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