BRG1 Stimulates Endothelial Derived Alarmin MRP8 to Promote Macrophage Infiltration in an Animal Model of Cardiac Hypertrophy
BRG1 Stimulates Endothelial Derived Alarmin MRP8 to Promote Macrophage Infiltration in an Animal Model of Cardiac Hypertrophy
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BRG1 刺激内皮源性警报蛋白 MRP8 促进心脏肥大动物模型中的巨噬细胞浸润
DOI：
10.3389/fcell.2020.00569
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发表时间：
2020-07-07
影响因子：
5.5
通讯作者：
Xu, Yong
中科院分区：
文献类型：
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作者：
Li, Zilong;Zhang, Yuanyuan;Xu, Yong
血管内皮细胞衍生的血管分泌因子参与了机体内环境平衡的破坏和心血管疾病对应激刺激的反应。在本研究中，我们研究了染色质重塑复合体的关键成分BRG1在调节血管分泌信号中的作用。我们报道血管紧张素II(Ang II)诱导的病理性心肌肥厚在内皮特异性BRG1消融(ECKO)小鼠(ECKO)与对照小鼠(WT)相比有所减轻。BRG1缺乏导致的心肌肥厚的缓解伴随着巨噬细胞归巢到心脏的减少。这可以通过观察到与WT小鼠相比，ECKO小鼠血管内皮细胞中髓系相关蛋白8(MRP8)的下调可以解释这一现象，MRP8是一种成熟的巨噬细胞趋化因子。进一步分析表明，BRG1通过Ang II处理内皮细胞，激活MRP8的表达，从而促进巨噬细胞的迁移。BRG1通过与缺氧诱导因子1(HIF-1α)相互作用被招募到MRP8启动子。反过来，BRG1通过依次募集组蛋白乙酰转移酶p300和组蛋白去甲基酶KDM3A促进HIF-1α与MRP8启动子的结合。去除p300或KDM3A均可抑制Ang II诱导的MRP8表达，并改善巨噬细胞的迁移。总之，我们的数据描绘了一条新的表观遗传学途径，通过Ang II刺激MRP8的产生和巨噬细胞归巢来促进心肌肥厚。
Endothelial cell derived angiocrine factors contribute to the disruption of homeostasis and the pathogenesis of cardiovascular diseases in response to stress stimuli. In the present study we investigated the role of BRG1, a key component of the chromatin remodeling complex, in the regulation of angiocrine signaling. We report that angiotensin II (Ang II) induced pathological cardiac hypertrophy was attenuated in mice with endothelial-specific ablation of BRG1 (ecKO) compared to the control mice (WT). Mitigation of cardiac hypertrophy as a result of BRG1 deficiency was accompanied by decreased macrophage homing to the hearts. This could be explained by the observation that the ecKO mice exhibited down-regulation of myeloid-related protein 8 (MRP8), a well-established chemokine for macrophages, in vascular endothelial cells compared to the WT mice. Further analysis revealed that BRG1 mediated the activation of MRP8 expression by Ang II treatment in endothelial cells to promote macrophage migration. BRG1 was recruited to the MRP8 promoter by interacting with hypoxia-inducible factor 1 (HIF-1 alpha). Reciprocally, BRG1 facilitated the binding of HIF-1 alpha to the MRP8 promoter by sequentially recruiting histone acetyltransferase p300 and histone demethylase KDM3A. Depletion of either p300 or KDM3A repressed the induction of MRP8 expression by Ang II and ameliorated macrophage migration. In conclusion, our data delineate a novel epigenetic pathway whereby Ang II stimulates MRP8 production and macrophage homing to promote cardiac hypertrophy.