DNA hypermethylation: A novel mechanism of CREG gene suppression and atherosclerogenic endothelial dysfunction
| Autor: | Li Yang, Meili Liu, Xiaoxiang Tian, Yaling Han, Chenghui Yan, Yanxia Liu, Dan Liu, Shan Liu, Zhang Xiaolin |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Endothelium Clinical Biochemistry Biology Biochemistry DNA methyltransferase Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine medicine Human Umbilical Vein Endothelial Cells Humans Epigenetics Endothelial dysfunction lcsh:QH301-705.5 Transcription factor lcsh:R5-920 Organic Chemistry Promoter Nitric oxide Methylation DNA DNA Methylation CREG medicine.disease Atherosclerosis Lipoproteins LDL Repressor Proteins 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) DNA methylation Cancer research lcsh:Medicine (General) 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Redox Biology Redox Biology, Vol 32, Iss, Pp-(2020) |
| ISSN: | 2213-2317 |
| Popis: | Objective Cellular repressor of E1A-stimulated genes (CREG), a vasculoprotective molecule, is significantly downregulated in atherosclerotic vessels through unclear mechanisms. While epigenetic regulation is involved in atherosclerosis development, it is not known if the CREG gene is epigenetically regulated. The aim of this study was to assess the potential role of CREG methylation in contributing to atherosclerosis. Approach and results Overexpression of DNA methyltransferase (DNMT)3B significantly inhibited CREG expression in human umbilical vein endothelial cells (HUVECs) and human coronary aortic endothelial cells (HCAECs).Conversely, inhibition of DNA methylation with 5-aza-2′-deoxycytidine (5-aza-dC) dose-dependently increased CREG expression. A CREG promoter analysis identified +168 to +255 bp as a key regulatory region and the CG site at +201/+202 bp as a key methylation site. The transcription factor GR-α could bind to the +201/+202 bp CG site promoting CREG transcription, a process significantly inhibited by DNMT3B overexpression. Treatment of cells with oxidized low-density lipoprotein (ox-LDL), a critical atherosclerogenic factor, significantly increased DNMT3B expression, increasing CREG promotor methylation, blocking GR-α binding, and inhibiting CREG expression. Consistently, CG sites in the CREG promoter fragment were hyper-methylated in human atherosclerotic arteries, and CREG expression was significantly reduced. A negative correlation between DNMT3B and CREG expression levels was observed in human atherosclerotic arteries. Finally, Ox-LDL-induced endothelium dysfunction was significantly attenuated by both 5-aza-dC and an anti-oxidative molecular N-acetylcysteine (NAC) administration through rescue the expression of CREG and activation of the p-eNOS/NO pathway. Conclusions Our study provides the first direct evidence that DNMT3B-mediated CREG gene hypermethylation is a novel mechanism that contributes to endothelial dysfunction and atherosclerosis development. Blocking CREG methylation may represent a novel therapeutic approach to treat ox-LDL-induced atherosclerosis. Highlights • Overexpression of DNMT3B but not DNMT1 or DNMT3A in HUVECs inhibits CREG expression. • The CREG promoter contains a key methylation CG site at +201/+202 bp. • GR-α can bind to the +201/+202 bp site to promote CREG transcription. • Blocking CREG methylation may represent a novel therapeutic approach to treat ox-LDL-induced atherosclerosis. |
| Databáze: | OpenAIRE |
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