Reciprocal Regulation Between miR-148a/152 and DNA Methyltransferase 1 Is Associated with Hyperhomocysteinemia-Accelerated Atherosclerosis
Reciprocal Regulation Between miR-148a/152 and DNA Methyltransferase 1 Is Associated with Hyperhomocysteinemia-Accelerated Atherosclerosis
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miR-148a/152 和 DNA 甲基转移酶 1 之间的相互调节与高同型半胱氨酸血症加速动脉粥样硬化有关
DOI：
10.1089/dna.2017.3651
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发表时间：
2017-06-01
影响因子：
3.1
通讯作者：
Jiang, Yideng
中科院分区：
文献类型：
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作者：
Yang, Anning;Sun, Yue;Jiang, Yideng
DNA 甲基转移酶 1 (DNMT1) 和 miRNA 都是基因表达的重要调节因子，与动脉粥样硬化的发病机制有关。本研究旨在阐明 DNMT1 和 miRNA 在高同型半胱氨酸血症 (HHcy) 相关动脉粥样硬化背景下的潜在相互作用。在喂食高蛋氨酸饮食的 ApoE(-/-) 小鼠的主动脉中，检测到 miR-148a/152 表达增加，而 DNMT1 mRNA 和蛋白质水平降低。在用同型半胱氨酸刺激的培养泡沫细胞中观察到类似的变化。当使用病毒载体过表达miR-148a/152时，培养的泡沫细胞中DNMT1表达受到抑制，而脂肪分化相关蛋白（ADRP）表达增强，总胆固醇（TC）和胆固醇酯（CE）含量增加。相反，miR-148a/152的下调导致DNMT1表达升高，ADRP表达降低，TC和CE含量降低。荧光素酶报告基因检测证实DNMT1是miR-148a/152的靶基因，并且DNMT1的过表达可以部分逆转miR-148a/152诱导的泡沫细胞中的脂质积累。同时，我们观察到 DNMT1 过表达增强了 DNA 甲基化并降低了 miR-148a/152 的表达。我们的数据显示泡沫细胞中 miR-148a/152 和 DNMT1 之间的相互调节，这可能在 HHcy 相关动脉粥样硬化中发挥关键作用。
DNA methyltransferase 1 (DNMT1) and miRNAs are both important regulators of gene expression that have been implicated in the pathogenesis of atherosclerosis. This study was designed to elucidate the potential interaction between DNMT1 and miRNAs in the context of hyperhomocysteinemia (HHcy)-related atherosclerosis. In the aorta of ApoE(-/-) mice fed a high methionine diet, increased expression of miR-148a/152, with decreased DNMT1 mRNA and protein levels, was detected. Similar changes were observed in cultured foam cells stimulated with homocysteine. When miR-148a/152 was overexpressed using viral vectors, DNMT1 expression was suppressed, whereas the expression of adipose differentiation-related protein (ADRP) was enhanced, and the contents of total cholesterol (TC) and cholesteryl ester (CE) were increased in cultured foam cells. Conversely, downregulation of miR-148a/152 led to elevated DNMT1 expression, reduced ADRP expression, and lowered contents of TC and CE. The luciferase reporter assay verified that DNMT1 is a target gene for miR-148a/152 and overexpression of DNMT1 can partially reverse the miR-148a/152-induced lipid accumulation in foam cells. Meanwhile, we observed that DNMT1 overexpression enhanced DNA methylation and reduced miR-148a/152 expression. Our data showed reciprocal regulation between miR-148a/152 and DNMT1 in foam cells, which likely plays a critical role in HHcy-related atherosclerosis.