MicroRNA-Mediated Epigenetic Silencing of Sirtuin1 Contributes to Impaired Angiogenic Responses
MicroRNA-Mediated Epigenetic Silencing of Sirtuin1 Contributes to Impaired Angiogenic Responses
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DOI：
10.1161/circresaha.113.301702
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发表时间：
2013-09-27
影响因子：
20.1
通讯作者：
Thum, Thomas
中科院分区：
文献类型：
--
作者：
Volkmann, Ingo;Kumarswamy, Regalla;Thum, Thomas
基本原理：转化生长因子 (TGF) - 与血管功能异常有关，并可介导内皮血管生成反应受损。在这种情况下，其对 microRNA 和下游靶标的影响尚不清楚。目的：研究 microRNA 在 TGF 介导的血管生成活性中的作用。方法和结果：TGF 处理内皮细胞后的 MicroRNA 分析发现 miR-30a-3p 以及 miR-30 家族的其他成员被强烈沉默。补充 miR-30a-3p 可恢复 TGF 处理的内皮细胞的功能。我们确定表观遗传因子甲基 CpG 结合蛋白 2 (MeCP2) 是 miR-30a-3p 的直接功能靶标。 MeCP2 的病毒过度表达模仿了 TGF-β 的作用，表明 TGF-β 治疗后 MeCP2 的去抑制可能是导致血管生成反应受损的原因。 MeCP2 的沉默可挽救 TGF-β 对内皮细胞的有害作用。对 MeCP2 过表达内皮细胞的微阵列转录组分析发现了几个对内皮细胞功能重要的失调基因，包括 Sirtuin1 (Sirt1)。使用内皮细胞特异性 MeCP2 null 或 Sirt1 转基因小鼠进行的体内实验证实了 MeCP2/Sirt1 参与内皮细胞血管生成功能的调节。其他实验发现，MeCP2 部分通过 Sirt1 的表观遗传沉默来抑制内皮血管生成特征。结论：TGF-β 部分通过下调 miR-30a-3p 以及随后 MeCP2 介导的 Sirt1 表观遗传沉默的去抑制来损害内皮血管生成反应。
Rationale: Transforming growth factor (TGF)- was linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses. Its effect on microRNAs and downstream targets in this context is not known.Objective: To study the role of microRNAs in TGF--mediated angiogenic activity.Methods and Results: MicroRNA profiling after TGF- treatment of endothelial cells identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. Supplementation of miR-30a-3p restored function in TGF--treated endothelial cells. We identified the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p. Viral overexpression of MeCP2 mimicked the effects of TGF-, suggesting that derepression of MeCP2 after TGF- treatment may be responsible for impaired angiogenic responses. Silencing of MeCP2 rescued detrimental TGF- effects on endothelial cells. Microarray transcriptome analysis of MeCP2-overexpressing endothelial cells identified several deregulated genes important for endothelial cell function including sirtuin1 (Sirt1). In vivo experiments using endothelial cell-specific MeCP2 null or Sirt1 transgenic mice confirmed the involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells. Additional experiments identified that MeCP2 inhibited endothelial angiogenic characteristics partly by epigenetic silencing of Sirt1.Conclusions: TGF- impairs endothelial angiogenic responses partly by downregulating miR-30a-3p and subsequent derepression of MeCP2-mediated epigenetic silencing of Sirt1.