Cui Shanshan, Li Wen, Lv Xin, Wang Pengyan, Gao Yuxia, Huang Guowei
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin 300052, China.
Int J Mol Sci. 2017 May 5;18(5):990. doi: 10.3390/ijms18050990.
The pathogenesis of atherosclerosis has been partly acknowledged to result from aberrant epigenetic mechanisms. Accordingly, low folate levels are considered to be a contributing factor to promoting vascular disease because of deregulation of DNA methylation. We hypothesized that increasing the levels of folic acid may act via an epigenetic gene silencing mechanism to ameliorate atherosclerosis. Here, we investigated the atheroprotective effects of folic acid and the resultant methylation status in high-fat diet-fed ApoE knockout mice and in oxidized low-density lipoprotein-treated human umbilical vein endothelial cells. We analyzed atherosclerotic lesion histology, folate concentration, homocysteine concentration, -adenosylmethionine (SAM) and -adenosylhomocysteine (SAH), and DNA methyltransferase activity, as well as monocyte chemotactic protein-1 (MCP1) and vascular endothelial growth factor (VEGF) expression and promoter methylation. Folic acid reduced atherosclerotic lesion size in ApoE knockout mice. The underlying folic acid protective mechanism appears to operate through regulating the normal homocysteine state, upregulating the SAM: SAH ratio, elevating DNA methyltransferase activity and expression, altering MCP1 and VEGF promoter methylation, and inhibiting MCP1 and VEGF expression. We conclude that folic acid supplementation effectively prevented atherosclerosis by modifying DNA methylation through the methionine cycle, improving DNA methyltransferase activity and expression, and thus changing the expression of atherosclerosis-related genes.
动脉粥样硬化的发病机制部分被认为是由异常的表观遗传机制引起的。因此，由于DNA甲基化失调，低叶酸水平被认为是促进血管疾病的一个因素。我们假设增加叶酸水平可能通过表观遗传基因沉默机制来改善动脉粥样硬化。在此，我们研究了叶酸在高脂饮食喂养的ApoE基因敲除小鼠和氧化型低密度脂蛋白处理的人脐静脉内皮细胞中的抗动脉粥样硬化作用及由此产生的甲基化状态。我们分析了动脉粥样硬化病变组织学、叶酸浓度、同型半胱氨酸浓度、S-腺苷甲硫氨酸（SAM）和S-腺苷同型半胱氨酸（SAH）、DNA甲基转移酶活性，以及单核细胞趋化蛋白-1（MCP1）和血管内皮生长因子（VEGF）的表达和启动子甲基化。叶酸减小了ApoE基因敲除小鼠的动脉粥样硬化病变大小。潜在的叶酸保护机制似乎是通过调节正常的同型半胱氨酸状态、上调SAM:SAH比值、提高DNA甲基转移酶活性和表达、改变MCP1和VEGF启动子甲基化以及抑制MCP1和VEGF表达来发挥作用。我们得出结论，补充叶酸通过甲硫氨酸循环改变DNA甲基化、提高DNA甲基转移酶活性和表达，从而改变动脉粥样硬化相关基因的表达，有效预防了动脉粥样硬化。
