Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, China.
J Mol Cell Cardiol. 2018 Dec;125:6-17. doi: 10.1016/j.yjmcc.2018.10.012. Epub 2018 Oct 16.
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 (CaCl). 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.
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内环境稳定方面发挥着关键作用。当这些因子失调时，它们可能导致生理完整性的破坏，并促进许多不同组织和器官的疾病发生。在本研究中，我们研究了内皮细胞中染色质重塑蛋白 brahma 相关基因 1（Brg1）的靶向缺失如何影响氯化钙（CaCl）诱导的腹主动脉瘤（AAA）的发病机制。我们在这里报告，与野生型（WT）同窝仔相比，内皮细胞条件性 Brg1 敲除（ecKO）小鼠表现出 AAA 的表型减弱。免疫染色和定量 PCR 分析表明，血管炎症在 ecKO 小鼠中受到抑制，而在 WT 小鼠中则相反，这可能是由于巨噬细胞的募集减少所致。进一步的检查表明，Brg1 缺失导致集落刺激因子 1（CSF1）水平降低。在培养的内皮细胞中，Brg1 与组蛋白 H3K9 去甲基化酶 KDM3A 合作激活 CSF1 转录和巨噬细胞募集，从而使血管炎症持续存在。内皮细胞中 BRG1 或 KDM3A 的耗竭可抑制 CSF1 的产生并减弱巨噬细胞趋化性。因此，我们的数据表明，Brg1 通过表观遗传激活 CSF1 转录可能有助于 AAA 的发病机制。
