Aberrant DNA methylation of the PDGF gene in homocysteine-mediated VSMC proliferation and its underlying mechanism
Aberrant DNA methylation of the PDGF gene in homocysteine-mediated VSMC proliferation and its underlying mechanism
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DOI：
10.3892/mmr.2014.2249
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发表时间：
2014-08-01
影响因子：
3.4
通讯作者：
Xu, Hua
中科院分区：
文献类型：
--
作者：
Han, Xue-Bo;Zhang, Hui-Ping;Xu, Hua
同型半胱氨酸（homocysteine，Hcy）是以血管平滑肌细胞（vascular smooth muscle cell，VSMC）增殖为特征的动脉粥样硬化（atherosclerosis，AS）的独立危险因子。然而，AS在VSMCs中的分子机制尚未阐明。本研究旨在探讨血小板源性生长因子（PDGF）基因异常甲基化在Hcy介导的VSMC增殖中的作用及其机制。培养的人VSMCs用不同浓度的Hcy处理。VSMC增殖、PDGF mRNA和蛋白表达以及PDGF启动子去甲基化均随Hey浓度呈剂量依赖性增加，表明它们之间存在相关性。细胞周期分析显示，Hey处理后，VSMC处于G（0）/G（1）期的细胞比例减少，S期细胞比例增加，表明Hey处理后VSMC增殖增加。此外，观察到S-腺苷高半胱氨酸（SAH）水平升高，S-腺苷甲硫氨酸（SAM）水平降低。SAM/SAH比值的降低可能部分解释了Hey处理后PDGF的低甲基化。叶酸处理对Hey诱导的VSMC增殖、异常PDGF甲基化和PDGF表达表现出拮抗作用。这些数据表明，Hey可能通过影响PDGF的表观遗传调控，通过其启动子区域的去甲基化，通过PDGF信号通路刺激VSMC增殖。这些发现可能提供了新的见解异常PDGF基因去甲基化和血管平滑肌细胞增殖之间的分子关联在Hey相关的AS。
It is well established that homocysteine (Hcy) is an independent risk factor for atherosclerosis (AS), which is characterized by vascular smooth muscle cell (VSMC) proliferation. However, the molecular mechanism underlying AS in VSMCs is yet to be elucidated. The aim of this study was to investigate the potential involvement of aberrant DNA methylation of the platelet-derived growth factor (PDGF) gene in Hcy-mediated VSMC proliferation and its underlying mechanism. Cultured human VSMCs were treated with varying concentrations of Hcy. VSMC proliferation, PDGF mRNA and protein expression and PDGF promoter demethylation showed a dose-dependent increase with Hey concentration, suggesting an association among them. Cell cycle analysis revealed a decreased proportion of VSMCs in G(0)/G(1) and an increased proportion in S phase, indicating that VSMC proliferation was increased under Hey treatment. Furthermore, S-adenosylhomocysteine (SAH) levels were observed to increase and those of S-adenosylmethionine (SAM) were observed to decrease. The consequent decrease in the ratio of SAM/SAH may partially explain the hypomethylation of PDGF with Hey treatment. Folate treatment exhibited an antagonistic effect against Hey-induced VSMC proliferation, aberrant PDGF methylation and PDGF expression. These data suggest that Hey may stimulate VSMC proliferation through the PDGF signaling pathway by affecting the epigenetic regulation of PDGF through the demethylation of its promoter region. These findings may provide novel insight into the molecular association between aberrant PDGF gene demethylation and the proliferation of VSMCs in Hey-associated AS.