Brg1 trans-activates endothelium-derived colony stimulating factor to promote calcium chloride induced abdominal aortic aneurysm in mice.
Brg1 trans-activates endothelium-derived colony stimulating factor to promote calcium chloride induced abdominal aortic aneurysm in mice.
复制标题
DOI：
10.1016/j.yjmcc.2018.10.012
复制
发表时间：
2018-10
影响因子：
5
通讯作者：
Xinjian Zhang;Shuai Liu;X. Weng;Teng Wu;Liming Yu;Yong Xu;Junli Guo
中科院分区：
文献类型：
--
作者：
Xinjian Zhang;Shuai Liu;X. Weng;Teng Wu;Liming Yu;Yong Xu;Junli Guo
内皮细胞衍生的分泌因子通过影响其他细胞的行为，在维持动态平衡方面发挥着关键作用。当调节失调时，这些因素可能会破坏生理完整性，并促进许多不同组织和器官的疾病发生。本研究探讨了血管内皮细胞染色质重塑蛋白Brahma相关基因1(BRG1)的靶向缺失对氯化钙(CaCl2)诱导的腹主动脉瘤(AAA)发病的影响。我们在这里报道，与野生型(WT)小鼠相比，内皮条件BRG1基因敲除(ECKO)小鼠表现出减弱的AAA表型。免疫染色和定量PCR分析表明，与WT小鼠相比，ECKO小鼠的血管炎症受到抑制，这可能是由于巨噬细胞募集减少所致。进一步检查发现BRG1缺乏导致集落刺激因子1(CSF1)水平降低。在培养的内皮细胞中，BRG1与组蛋白H3K9去甲基酶KDM3A协同激活CSF1转录和巨噬细胞募集，从而持续血管炎症。内皮细胞中BRG1或KDM3A的缺失抑制了CSF1的产生，并减弱了巨噬细胞的趋化作用。因此，我们的数据提示BRG1对CSF1转录的表观激活可能参与了AAA的发病。
Endothelial cell derived secretive factors play pivotal roles maintaining the homeostasis by influencing the behaviors of other cells. When dysregulated, these factors may contribute to the disruption of physiological integrity and promote disease genesis in a number of different tissues and organs. In the present study we investigated how targeted deletion of brahma related gene 1 (Brg1), a chromatin remodeling protein, in endothelium might affect the pathogenesis of abdominal aortic aneurysm (AAA) induced by calcium chloride (CaCl2). We report here that compared to the wild type (WT) littermates, endothelial conditional Brg1 knockout (ecKO) mice exhibited an attenuated phenotype of AAA. Immunostaining and quantitative PCR analyses showed that vascular inflammation was suppressed in ecKO mice as opposed to WT mice likely due to diminished recruitment of macrophages. Further examination revealed that Brg1 deficiency led to a reduction in colony stimulating factor 1 (CSF1) levels. In cultured endothelial cells, Brg1 cooperated with histone H3K9 demethylase KDM3A to activate CSF1 transcription and macrophage recruitment thereby perpetuating vascular inflammation. Depletion of BRG1 or KDM3A in endothelial cells dampened CSF1 production and attenuated macrophage chemotaxis. Therefore, our data suggest that epigenetic activation of CSF1 transcription by Brg1 may contribute to AAA pathogenesis.