Homocysteine inhibits endothelial progenitor cells proliferation via DNMT1-mediated hypomethylation of Cyclin A
Homocysteine inhibits endothelial progenitor cells proliferation via DNMT1-mediated hypomethylation of Cyclin A
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同型半胱氨酸通过 DNMT1 介导的 Cyclin A 低甲基化抑制内皮祖细胞增殖
DOI：
10.1016/j.yexcr.2017.11.021
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发表时间：
2018
影响因子：
3.7
通讯作者：
Jiang Yi Deng
中科院分区：
文献类型：
--
作者：
Zhang Hui Ping;Wang Yan Hua;Ma Sheng Chao;Zhang Hui;Yang An Ning;Yang Xiao Ling;Zhang Ming Hao;Sun Jian Min;Hao Yin Ju;Jiang Yi Deng
内皮祖细胞 (EPC) 有助于受损血管的新血管生成和再内皮化，以维持内皮细胞。 EPCs 功能障碍与同型半胱氨酸 (Hcy) 诱导的血管损伤的发病机制有关。我们的目的是研究Cyclin A在Hcy诱导的EPCs功能障碍中的作用并探讨其分子机制。在本研究中，通过Hcy处理EPC，我们发现Cyclin A mRNA和蛋白的表达以剂量依赖性方式显着下调。 Cyclin A的敲低显着降低了EPC的增殖，而Cyclin A的过表达则显着促进了细胞增殖，表明Hcy通过下调Cyclin A的表达来抑制EPC的增殖。此外，表观遗传学研究还表明，Hcy通过下调DNMT1的表达，诱导EPCs中Cyclin A启动子的DNA低甲基化。此外，我们发现EPCs的Hcy处理导致SAM、SAH和MeCP2增加，而SAM/SAH比值和MBD表达降低。总之，我们的结果表明，Hcy 通过 Cyclin A 的低甲基化来抑制 Cyclin A 的表达，从而抑制 EPC 增殖。这些发现证明了 DNMT1 介导的 DNA 甲基化预防 Hcy 相关心血管疾病的新机制。
Endothelial progenitor cells (EPCs) contribute to neovasculogenesis and reendothelialization of damaged blood vessels to maintain the endothelium. Dysfunction of EPCs is implicated in the pathogenesis of vascular injury induced by homocysteine (Hcy). We aimed to investigate the role of Cyclin A in Hcy-induced EPCs dysfunction and explore its molecular mechanism. In this study, by treatment of EPCs with Hcy, we found that the expression of Cyclin A mRNA and protein were significantly downregulated in a dose-dependent manner. Knockdown of Cyclin A prominently reduced proliferation of EPCs, while over-expression of Cyclin A significantly promoted the cell proliferation, suggesting that Hcy inhibits EPCs proliferation through downregulation of Cyclin A expression. In addition, epigenetic study also demonstrated that Hcy induces DNA hypomethylation of the Cyclin A promoter in EPCs through downregulated expression of DNMT1. Moreover, we found that Hcy treatment of EPCs leads to increased SAM, SAH and MeCP2, while the ratio of SAM/SAH and MBD expression decrease. In summary, our results indicate that Hcy inhibits Cyclin A expression through hypomethylation of Cyclin A and thereby suppress EPCs proliferation. These findings demonstrate a novel mechanism of DNA methylation mediated by DNMT1 in prevention of Hcy associated cardiovascular disease.