Homocysteine induces vascular inflammatory response via SMAD7 hypermethylation in human umbilical vein smooth muscle cells
Homocysteine induces vascular inflammatory response via SMAD7 hypermethylation in human umbilical vein smooth muscle cells
复制标题
同型半胱氨酸通过人脐静脉平滑肌细胞中 SMAD7 高甲基化诱导血管炎症反应。
DOI：
10.1016/j.mvr.2018.05.003
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发表时间：
2018-11-01
影响因子：
3.1
通讯作者：
Li, Yuan-yuan
中科院分区：
文献类型：
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作者：
Wei, Li-hua;Chao, Nai-xia;Li, Yuan-yuan
同型半胱氨酸（Homocysteine，Hcy）可通过炎症反应和DNA甲基化紊乱诱导动脉粥样硬化。我们最近的研究报道了一个新的与动脉粥样硬化相关的表观遗传修饰基因SMAD 7。为进一步了解动脉粥样硬化的发病机制，本研究旨在探讨同型半胱氨酸（Hcy）通过干扰SMAD 7甲基化对人脐静脉平滑肌细胞（HUVSMCs）的炎症作用。利用MALDI-TOF MS技术，我们发现Hcy以剂量和时间依赖的方式增加HUVSMCs SMAD 7启动子的DNA甲基化水平。SMAD 7 mRNA和蛋白表达水平均随着Hcy浓度的增加和作用时间的延长而沿着下降。SMAD 7水平降低导致HUVSMC中促炎细胞因子（TNF-α和IL-1 β）表达上调。此外，我们发现NF-κ B B通路的激活是Smad 7水平降低增强血管炎症的机制。因此，Hcy能够通过诱导HUVSMCs中SMAD 7启动子的高甲基化来激活NF-κ B介导的血管炎症反应。体外研究结果补充了我们最近的临床研究，SMAD 7甲基化作为动脉粥样硬化的新标志物，并进一步阐明了Hcy在动脉粥样硬化形成中的作用。
Homocysteine (Hcy) can induce atherosclerosis through the inflammatory response and DNA methylation disorder. Our recent study has reported a novel epigenetic modified gene related to atherosclerosis -SMAD7. To further understand the pathogenesis of atherosclerosis, the current study was designed to investigate an inflammatory role of Hcy in human umbilical vein smooth muscle cells (HUVSMCs) through interfering with SMAD7 methylation. Using MALDI-TOF MS, we found that Hcy increased DNA methylation levels of SMAD7 promoter in a dose and time-dependent manner in HUVSMCs. Meanwhile, both SMAD7 mRNA and protein levels were decreased along with the increase of Hcy concentrations and treating time. Decreased SMAD7 levels led to up regulation of pro-inflammatory cytokines (TNF-alpha and IL-1 beta) expression in HUVSMCs. Furthermore, we found that activation of NF-kappa B pathway was the mechanism by which reduced Smad7 levels enhanced vascular inflammation. Thus, Hcy is able to activate NF-kappa B-mediated vascular inflammatory response via inducing hypermethylation of SMAD7 promoter in HUVSMCs. The in vitro findings supplement our recent clinical study that SMAD7 methylation as a novel marker in atherosclerosis and further elucidate the role of Hcy in atherogenesis.