Aberrant MFN2 transcription facilitates homocysteine-induced VSMCs proliferation via the increased binding of c-Myc to DNMT1 in atherosclerosis
Aberrant MFN2 transcription facilitates homocysteine-induced VSMCs proliferation via the increased binding of c-Myc to DNMT1 in atherosclerosis
复制标题
动脉粥样硬化中异常的 MFN2 转录通过增加 c-Myc 与 DNMT1 的结合促进同型半胱氨酸诱导的 VSMC 增殖
DOI：
10.1111/jcmm.14341
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发表时间：
2019-07-01
影响因子：
5.3
通讯作者：
Jiang, Yideng
中科院分区：
文献类型：
--
作者：
Xu, Long;Hao, Hongyi;Jiang, Yideng
同型半胱氨酸（homocysteine，Hcy）是动脉粥样硬化的独立危险因素。同型半胱氨酸可促进血管平滑肌细胞（VSMC）增殖，在新生内膜形成中起关键作用，从而促进动脉硬化。然而，动脉粥样硬化中VSMCs增殖的分子机制尚未完全阐明。线粒体融合蛋白2（Mitofusin-2，MFN 2）是线粒体外膜上一种重要的跨膜谷胱甘肽转移酶，可将细胞阻滞在细胞周期的G 0/G1期。探讨MFN 2基因转录异常在同型半胱氨酸诱导的血管平滑肌细胞增殖中的作用及其机制。细胞周期分析显示，高同型半胱氨酸血症（hyperhomocystinaemia，HHcy）的APOE（-/-）小鼠动脉粥样硬化斑块中G 0/G1期VSMCs比例减少，S期VSMCs比例增加。同型半胱氨酸处理的VSMCs中，MFN 2基因启动子区DNA甲基化水平明显升高，导致MFN 2基因启动子区活性降低，MFN 2基因表达降低。此外，我们还发现同型半胱氨酸处理的动脉粥样硬化斑块和VSMCs中c-Myc的表达增加。进一步研究表明，c-Myc通过与DNMT 1启动子结合，上调DNMT 1表达，导致MFN 2启动子DNA甲基化，从而抑制Hcy处理的VSMCs中MFN 2的表达，从而间接调控MFN 2的表达。综上所述，我们的研究表明，Hcy诱导的MFN 2启动子甲基化抑制MFN 2的转录，导致VSMCs增殖形成斑块，c-Myc与DNMT 1启动子结合增加是一个新的相关分子机制。
It is well-established that homocysteine (Hcy) is an independent risk factor for atherosclerosis. Hcy can promote vascular smooth muscle cell (VSMC) proliferation, it plays a key role in neointimal formation and thus contribute to arteriosclerosis. However, the molecular mechanism on VSMCs proliferation underlying atherosclerosis is not well elucidated. Mitofusin-2 (MFN2) is an important transmembrane GTPase in the mitochondrial outer membrane and it can block cells in the G0/G1 stage of the cell cycle. To investigate the contribution of aberrant MFN2 transcription in Hcy-induced VSMCs proliferation and the underlying mechanisms. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase in atherosclerotic plaque of APOE(-/-) mice with hyperhomocystinaemia (HHcy) as well as in VSMCs exposed to Hcy in vitro. The DNA methylation level of MFN2 promoter was obviously increased in VSMCs treated with Hcy, leading to suppressed promoter activity and low expression of MFN2. In addition, we found that the expression of c-Myc was increased in atherosclerotic plaque and VSMCs treated with Hcy. Further study showed that c-Myc indirectly regulates MFN2 expression is duo to the binding of c-Myc to DNMT1 promoter up-regulates DNMT1 expression leading to DNA hypermethylation of MFN2 promoter, thereby inhibits MFN2 expression in VSMCs treated with Hcy. In conclusion, our study demonstrated that Hcy-induced hypermethylation of MFN2 promoter inhibits the transcription of MFN2, leading to VSMCs proliferation in plaque formation, and the increased binding of c-Myc to DNMT1 promoter is a new and relevant molecular mechanism.