Myocardin-Related Transcription Factor A Mediates OxLDL-Induced Endothelial Injury
Myocardin-Related Transcription Factor A Mediates OxLDL-Induced Endothelial Injury
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心肌素相关转录因子 A 介导 OxLDL 诱导的内皮损伤
DOI：
10.1161/circresaha.111.240655
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发表时间：
2011-04-01
影响因子：
20.1
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Fang, Fei;Yang, Yuyu;Xu, Yong
基本原理：动脉粥样硬化是一个多步骤的反应过程，首先是由一系列应激信号引起的内皮损伤，其中氧化低密度脂蛋白（oxLDL）起着关键作用。OxLDL通过上调粘附分子（例如ICAM-1）并伴随下调内皮一氧化氮合酶（eNOS）表达来破坏内皮的正常功能。介导细胞对oxLDL反应的转录调节因子在很大程度上仍不清楚。目的：我们的目标是确定是否心肌相关转录因子（MRTF）-A，一个关键的蛋白参与平滑肌细胞表型的转录调控，是负责内皮损伤的oxLDL，如果是这样，MRTF-A如何促进促动脉粥样硬化议程启动oxLDL。方法和结果：Western blotting和免疫荧光法证实OxLDL刺激内皮细胞MRTF-A的表达。过表达MRTF-A可协同增强oxLDL对ICAM-1的诱导和对eNOS的抑制。与此相反，破坏MRTF-A，无论是小干扰RNA或显性负突变，废除了致病程序引发的oxLDL。最后，染色质免疫沉淀试验表明，oxLDL优先增强MRTF-A结合ICAM-1和eNOS启动子和MRTF-A驱动的差异表观遗传学改变发生在这些启动子上响应oxLDL。结论：因此，我们的数据首次证明MRTF-A与血管内皮中的关键病理生理学事件密切相关。
Rationale: Atherosclerosis proceeds through a multistep reaction that begins with endothelial injury caused by a host of stress signals, among which oxidized low-density lipoprotein (oxLDL) plays a critical role. OxLDL disrupts normal functionality of the endothelium by upregulating adhesion molecules (eg, ICAM-1) and concomitantly downregulating endothelial nitric oxide synthase (eNOS) expression. The transcriptional modulator that mediates the cellular response to oxLDL remains largely obscure. Objective: Our goal was to determine whether myocardin-related transcription factor (MRTF)-A, a key protein involved in the transcriptional regulation of smooth muscle cell phenotype, is responsible for the endothelial injury by oxLDL, and, if so, how MRTF-A promotes the proatherogenic agenda initiated by oxLDL. Methods and Results: OxLDL stimulated the expression of MRTF-A in endothelial cells as evidenced by Western blotting and immunofluorescence. Overexpression of MRTF-A synergistically enhanced the induction of ICAM-1 and suppression of eNOS by oxLDL. In contrast, disruption of MRTF-A, either by small interfering RNA or dominant negative mutation, abrogated the pathogenic program triggered by oxLDL. Finally, chromatin immunoprecipitation assays indicate that oxLDL preferentially augmented MRTF-A binding to ICAM-1 and eNOS promoters and that MRTF-A drove differential epigenetic alterations taking place on these promoters in response to oxLDL. Conclusions: Therefore, our data provide the first demonstration that MRTF-A is critically linked to pivotal pathophysiological events in the vascular endothelium.