Transcriptional Activation of Matricellular Protein Spondin2 (SPON2) by BRG1 in Vascular Endothelial Cells Promotes Macrophage Chemotaxis
Transcriptional Activation of Matricellular Protein Spondin2 (SPON2) by BRG1 in Vascular Endothelial Cells Promotes Macrophage Chemotaxis
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BRG1 在血管内皮细胞中转录激活基质细胞蛋白 Spondin2 (SPON2)，促进巨噬细胞趋化性
DOI：
10.3389/fcell.2020.00794
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发表时间：
2020-08-14
影响因子：
5.5
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Li, Nan;Liu, Shuai;Xu, Yong
基质细胞蛋白SPON2在心血管疾病的发生发展中发挥着多种作用。SPON2在血管内皮细胞中表达，但其在动脉粥样硬化形成过程中的转录调控尚不完全清楚。在此，我们报道了促动脉粥样硬化刺激(oxLDL和肿瘤坏死因子-α)上调血管内皮细胞SPON2mRNA的表达。此外，与对照组相比，在以西方饮食喂养的APOE-/-小鼠中，内皮SPON_2升高。促动脉粥样硬化刺激对内皮细胞SPON2的诱导是由染色质重塑蛋白BRG1在体外和体内介导的。进一步分析表明，BRG1与序列特异性转录因子Egr-1相互作用，激活SPON2转录。BRG1通过调节SPON2启动子周围的染色质结构参与了SPON2的反式激活。在功能上，Egr-1/BRG1复合体激活SPON2转录为巨噬细胞运输提供了具有化学吸引力的信号。SPON2耗尽后，BRG1或Egr-1刺激内皮源性趋化信号迁移巨噬细胞的能力减弱。相反，重组SPON2在缺乏BRG1或Egr-1的情况下拯救了内皮细胞的化学吸引力。总之，我们的数据已经在内皮细胞中发现了一种新的转录级联，它可能潜在地促进巨噬细胞募集和导致动脉粥样硬化的血管炎症。
The matricellular protein SPON2 plays diverse roles in the development of cardiovascular diseases. SPON2 is expressed in endothelial cells, but its transcription regulation in the context of atherogenesis remains incompletely appreciated. Here we report that SPON2 expression was up-regulated by pro-atherogenic stimuli (oxLDL and TNF-α) in vascular endothelia cells. In addition, endothelial SPON2 was elevated in Apoe–/– mice fed on a Western diet compared to the control mice. Induction of SPON2 in endothelial cells by pro-atherogenic stimuli was mediated by BRG1, a chromatin remodeling protein, both in vitro and in vivo. Further analysis revealed that BRG1 interacted with the sequence-specific transcription factor Egr-1 to activate SPON2 transcription. BRG1 contributed to SPON2 trans-activation by modulating chromatin structure surrounding the SPON2 promoter. Functionally, activation of SPON2 transcription by the Egr-1/BRG1 complex provided chemoattractive cues for macrophage trafficking. SPON2 depletion abrogated the ability of BRG1 or Egr-1 to stimulate endothelial derived chemoattractive cue for macrophage migration. On the contrary, recombinant SPON2 rescued endothelial chemo-attractability in the absence of BRG1 or Egr-1. In conclusion, our data have identified a novel transcriptional cascade in endothelial cells that may potentially promote macrophage recruitment and vascular inflammation leading to atherogenesis.