Brg1 deficiency in vascular endothelial cells blocks neutrophil recruitment and ameliorates cardiac ischemia-reperfusion injury in mice.
Brg1 deficiency in vascular endothelial cells blocks neutrophil recruitment and ameliorates cardiac ischemia-reperfusion injury in mice.
复制标题
血管内皮细胞中的 Brg1 缺陷会阻碍中性粒细胞的募集并改善小鼠的心脏缺血再灌注损伤。
DOI：
10.1016/j.ijcard.2018.07.105
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Zhang X;Liu S;Weng X;Zeng S;Yu L;Guo J;Xu Y
背景：中性粒细胞浸润增加和随之而来的炎症反应是心脏缺血再灌注损伤(IRI)的标志性事件。方法和结果我们报道了染色质重塑蛋白Brahma相关基因1(BRG1)内皮特异性缺失的小鼠在心肌缺血-再灌流后表现出改善，表现为梗死面积缩小和心功能恢复更好。与野生型相比，内皮BRG1缺陷也可减轻IRI后的心肌纤维化。有趣的是，去除内皮细胞中的BRG1抑制了IRI后中性粒细胞的渗透，并下调了心脏中促炎症介质的水平。进一步研究发现，在缺氧-复氧(HR)条件下，BRG1能激活血管内皮细胞中对中性粒细胞黏附至关重要的L-选择素配体PODXL的转录。小干扰RNA敲除BRG1可抑制HR诱导的PODXL表达，并阻断中性粒细胞与内皮细胞的黏附。从机制上讲，BRG1通过与组蛋白H3K9去甲基酶JMJD2B相互作用，改变PODXL启动子周围的染色质结构。耗竭JMJD2B可阻断HR诱导的PODXL，并抑制中性粒细胞与内皮细胞的黏附。结论BRG1-JMJD2B复合体反式激活PODXL可促进中性粒细胞的浸润，从而促进心肌缺血再灌注损伤的发生。
BackgroundIncreased neutrophil infiltration and the ensuing inflammatory response represent a hallmark event in cardiac ischemia-reperfusion injury (IRI). It remains poorly defined how the epigenetic machinery contributes to this process.Methods and resultsHere we report that mice with endothelial specific deletion of brahma related gene 1 (BRG1), a chromatin remodeling protein, exhibited amelioration when subjected to cardiac ischemia-reperfusion as evidenced by a reduction in infarct size as well as better recovery of heart function. Endothelial BRG1 deficiency also attenuated cardiac fibrosis following IRI when compared to wild type littermates. Interestingly, ablation of BRG1 in the endothelium suppressed neutrophil infiltration and down-regulated the levels of pro-inflammatory mediators in the heart following IRI. Further studies revealed that BRG1 activated the transcription of PODOCALYXIN (PODXL), an L-SELECTIN ligand crucial for neutrophil adhesion, in vascular endothelial cells in response to hypoxia-reoxygenation (HR). BRG1 knockdown by small interfering RNA abrogated HR-induced PODXL expression and blocked the adhesion of neutrophils to endothelial cells. Mechanistically, BRG1 alters the chromatin structure surrounding the PODXL promoter by interacting with JMJD2B, a histone H3K9 demethylase. Depletion of JMJD2B abrogated PODXL induction by HR and inhibited the adhesion of neutrophils to endothelial cells.ConclusionOur data suggest that trans-activation of PODXL by the BRG1-JMJD2B complex in endothelial cells may promote neutrophil infiltration and consequently the pathogenesis of cardiac ischemia-reperfusion injury.
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影响因子：
2
作者：
R. Dmochowski
通讯作者：
R. Dmochowski
DOI：
10.1016/j.respe.2020.09.004
发表时间：
2020-10-10
期刊：
Revue D'Epidemiologie et De Sante Publique
影响因子：
--
作者：
La rédaction
通讯作者：
La rédaction
影响因子：
9.3
作者：
通讯作者：
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影响因子：
5.9
作者：
Craighead FL
通讯作者：
Craighead FL