Folate and ApoE DNA methylation induced by homocysteine in human monocytes
Folate and ApoE DNA methylation induced by homocysteine in human monocytes
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DOI：
10.1089/dna.2007.0619
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发表时间：
2007-10-01
影响因子：
3.1
通讯作者：
Wang Shu-Ren
中科院分区：
文献类型：
--
作者：
Jiang Yi-Deng;Sun Tao;Wang Shu-Ren
同型半胱氨酸（Hcy）是动脉硬化的重要独立危险因素，载脂蛋白E（ApoE）是抗动脉粥样硬化的重要基因，但其发病机制的特点及其关键环节仍知之甚少。本研究的目的是探讨Hcy和叶酸对ApoE的影响以及Hcy诱导单核细胞ApoE表达的潜在机制。当临床相关浓度的Hcy和叶酸添加到培养的单核细胞中4天时，我们发现临床相关的Hcy（100 mM）可能会增加总胆固醇（TC）、游离胆固醇（FC）和胆固醇酯（CE）的水平，并且还会降低ApoE mRNA、蛋白表达，导致培养的原代人单核细胞与阳性组相比分别为34.28%、45.00%。 Hcy的作用主要是由C-5 MTase介导的，因为Hcy可以上调C-5 MTase的活性，进而加速ApoE的DNA甲基化。然而，叶酸降低了 TC、FC 和 CE 的水平 (p < 0.001)，并增加了 ApoE 的表达；也就是说，叶酸主要抑制Hcy诱导的DNA甲基化作用，从而起到抗动脉粥样硬化的作用。总之，这些结果表明 Hcy 诱导的 ApoE DNA 甲基化可能在动脉粥样硬化中 ApoE 表达中发挥潜在作用。叶酸具有抗动脉粥样硬化的有益作用，可能成为预防 Hcy 诱导的动脉粥样硬化的治疗靶点。
Homocysteine (Hcy) is an important and independent risk factor for arteriosclerosis, and apolipoprotein E (ApoE) is an important gene of antiatherosclerosis, but the characteristics and their key links that are involved in their pathogenic mechanisms are still poorly understood. The objective of the present study was to investigate the effects of Hcy and folate on ApoE as well as the underlying mechanism of ApoE expression induced by Hcy in monocytes. When clinically relevant concentrations of Hcy and folate were added to the cultured monocytes for 4 days, we found that clinically relevant Hcy (100 mM) may increase the levels of total cholesterol (TC), free cholesterol (FC), and cholesteryl ester (CE), and also decrease ApoE mRNA, protein expressions, leading to 34.28%, 45.00% in cultured primary human monocytes in comparison to the positive group. The effects of Hcy were primarily mediated by C-5 MTase, because Hcy could upregulate the activity of C-5 MTase and then accelerate DNA methylation of ApoE. However, folate decreased the levels of TC, FC, and CE (p < 0.001) and increased the ApoE expression; as to say, folate primarily repressed the effects of DNA methylation induced by Hcy and educed antiatherosclerosis. In conclusion, these results suggested that ApoE DNA methylation that is induced by Hcy may play a potential role for ApoE expression in atherosclerosis. Folate has beneficial effects for antiatherosclerosis, and it may become a therapeutic target for preventing Hcy-induced atherosclerosis.