血管平滑肌细胞中MRTF-A 诱导表观遗传复合体激活由内皮素介导的促炎症转录
文献 MRTF-A steers an epigenetic complex to activate endothelin-induced pro-inflammatory transcription in vascular smooth muscle cells 于 2014年 发表在 Nulcleic Acids Research 原文链接
Abstract:
Endothelin (ET-1) was initially identified as a potent vasoconstrictor contributing to the maintenance of vascular rhythm. Later studies have implicated ET-1, when aberrantly up-regulated within the vasculature, in a range of human pathologies associated with disruption of vascular homeostasis. ET-1 has been shown to invoke strong pro-inflammatory response in vascular smooth muscle cells (VSMCs); the underlying mechanism, however, remains elusive. Here, we report that the transcriptional modulator MRTF-A mediates the activation of pro-inflammatory mediators by ET-1 in VSMCs. ET-1 increased nuclear enrichment and activity of MRTF-A in cultured VSMCs. MRTF-A silencing attenuated ET-1 induced synthesis and release of pro-inflammatory mediators including IL-6, MCP-1 and IL-1 likely as a result of diminished NF-κB activity. In addition, MRTF-A was indispensible for the accumulation of active histone modifications on the gene promoters. Of intrigue, MRTF-A interacted with and recruited ASH2, a component of the mammalian histone methyltransferase complex, to transactivate pro-inflammatory genes in response to ET-1 treatment. The chromatin remodeling proteins BRG1 and BRM were also required for ET-1-dependent induction of pro-inflammatory mediators by communicating with ASH2, a process dependent on MRTF-A. In conclusion, our data have identified a novel epigenetic complex responsible for vascular inflammation inflicted by ET-1.
摘要：
最初内皮缩血管肽1（ET-1）被当做一种有助于维持血管节律的强效血管收缩剂。后来的研究表明当血管内异常上调时，ET-1参与了一系列与血管内稳态破坏有关的人类疾病。在血管平滑肌细胞（VSMCs）中ET-1可以激发强烈的促炎反应，但是其中的机制尚未知晓。本研究揭示了转录调节因子MRTF-A通过ET-1介导了VSMC中促炎症介质的激活。在培养的VSMCs中ET-1可以提高核富集和MRTF-A活性。MRTF-A沉默抑制了ET-1诱导促炎介质的合成与释放，包括IL-6，MCP-1和IL-1，这可能是NF-κB活性下降的结果。此外，MRTF-A对于活性组蛋白修饰在基因启动子上的积累必不可少。如果MRTF-A与哺乳动物组蛋白甲基转移酶复合物的组分ASH2相互作用，通过对ET-1的反应激活促炎基因。染色质重塑蛋白brg 1和brm也是通过与ash 2通讯来诱导促炎症介质的内皮素-1依赖的蛋白。研究表明了这种新的表观遗传复合物对ET-1所致血管炎症的影响。
使用试剂原文信息：ELISA was performed using supernatant collected from cultured vascular endothelial cells or rat pulmonary artery homogenates according to manufacturer's instructions (USCN Life Sciences).