Local hypomethylation in atherosclerosis found in rabbit ec-sod gene
Local hypomethylation in atherosclerosis found in rabbit ec-sod gene
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DOI：
10.1161/01.atv.19.9.2171
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发表时间：
1999-09-01
影响因子：
8.7
通讯作者：
Ylä-Herttuala, S
中科院分区：
文献类型：
--
作者：
Laukkanen, MO;Mannermaa, S;Ylä-Herttuala, S
细胞外超氧化物歧化酶（EC-SOD）可保护动脉免受超氧阴离子的有害影响和动脉粥样硬化的发展。在本研究中，我们克隆并鉴定了兔ec-sod基因。我们在克隆序列中鉴定出 6 个兔 C 元件和 5 个 CpG 簇。 CpG 簇之一位于编码序列上。由于CpG簇是甲基化酸的潜在位点，可以解释突变的发生，因此使用直接基因组测序对位于编码序列CpG簇中的每个CpG二聚体的甲基化状态进行了表征。出乎意料的是，与正常主动脉内膜中层相比，在动脉粥样硬化主动脉中检测到ec-sod基因中甲基化CPG二核苷酸的量显着减少。尽管DNA甲基化的改变在恶性肿瘤中已得到很好的表征，但动脉粥样硬化中甲基化改变的存在尚未被研究，尽管这两种疾病的特征都是细胞过度增殖和基因表达的改变。通过高压液相色谱对正常和动脉粥样硬化主动脉中的全基因组甲基化进行进一步分析，发现与正常动脉相比，动脉粥样硬化主动脉中 5-甲基胞嘧啶 (5-mC) 含量有降低的趋势。动脉粥样硬化主动脉中的低甲基化水平与恶性肿瘤的低甲基化水平相同。虽然甲基化水平与 EC-SOD 表达之间的因果关系无法得到证实，但我们的研究结果表明 ec-sod 低甲基化与动脉粥样硬化的发展相关，并表明它可能影响 ec-sod 和其他可能参与动脉粥样硬化病变发展的基因的结构和功能。
Extracellular superoxide dismutase (EC-SOD) protects arteries against deleterious effects of superoxide anions and the development of atherosclerosis. In this study, we cloned and characterized rabbit ec-sod gene. We identified 6 rabbit C-elements and 5 CpG clusters in the cloned sequence. One of the CpG clusters is located on the coding sequence. Because CpG clusters are potential sites for methylation acid may explain the occurrence of mutations, methylation status of each of the CpG dimers located in the coding sequence CpG cluster was characterized using direct genomic sequencing, Unexpectedly, a marked reduction in the amount of methylated CPG dinucleotides in ec-sod gene was detected in atherosclerotic aortas as compared with normal aortic intima-media. Although alterations in DNA methylation are well characterized in malignant tumors, the presence of methylation changes in atherosclerosis has not been studied even though both diseases are characterized by excess cellular proliferation and alterations in gene expression. Further analysis of the whole genomic methylation by high-pressure liquid chromatography in normal and atherosclerotic aortas revealed a tendency for a decreased 5-methylcytosine (5-mC) content in atherosclerotic aortas as compared with normal arteries. Hypomethylation in atherosclerotic aortas occurred at the same level as has been reported from malignant tumors. Although a causal relationship between the methylation level and expression of EC-SOD cannot be proven, our results show that ec-sod hypomethylation is associated with the development of atherosclerosis and suggest that it may affect structure and function of ec-sod and other genes possibly involved in the development of atherosclerotic lesions.