Proinflammatory stimuli engage Brahma related gene 1 and Brahma in endothelial injury.
Proinflammatory stimuli engage Brahma related gene 1 and Brahma in endothelial injury.
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促炎性刺激使梵天相关的基因1和梵天在内皮损伤中。
DOI：
10.1161/circresaha.113.301296
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发表时间：
2013-09-27
影响因子：
20.1
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Fang F;Chen D;Yu L;Dai X;Yang Y;Tian W;Cheng X;Xu H;Weng X;Fang M;Zhou J;Gao Y;Chen Q;Xu Y
炎症引起的内皮功能障碍存在于多种心血管疾病中。在这一过程中的一个标志性事件是白细胞在转录水平上通过上调内皮细胞中的黏附分子(CAM)介导的白细胞聚集和黏附到血管壁。CAM反式激活的表观遗传学调节因子(S)及其潜在的病理生理学相关性仍未明确。我们的目标是确定BRG1和BRM参与CAM反式激活及其在动脉粥样硬化发病机制中的相关性。在本研究中，我们报道了促炎刺激在体外增强了BRG1和BRM在体外培养的内皮细胞中的表达，并在体内增强了啮齿动物动脉中BRG1和BRM的表达。BRG1和BRM的过表达促进了炎症信号的诱导，而BRG1和BRM的敲除则抑制了炎症信号诱导的黏附分子的反式激活和白细胞的黏附。BRg1和BRm通过NF-κB/p65与CAM启动子相互作用并被募集到启动子中。相反，BRG1和BRM的缺失破坏了p65与CAM启动子的结合动力学，并削弱了CAM的激活。BRG1和BRM的沉默也改变了与CAM反式激活相关的关键表观遗传学变化。有趣的是，17β-雌二醇可拮抗BRG_1/BRM的表达和活性。最重要的是，内皮靶向的BRG1/BRM的消除赋予了西方饮食的apoE−/−小鼠动脉粥样硬化保护作用。因此，我们的数据表明，BRG1和BRM将各种促炎信号整合到CAM的反式激活和内皮功能障碍中，因此可能成为治疗炎症相关心血管疾病的潜在靶点。
Endothelial dysfunction inflicted by inflammation is found in a host of cardiovascular pathologies. One hallmark event in this process is the aggregation and adhesion of leukocyte to the vessel wall mediated by the up-regulation of adhesion molecules (CAM) in endothelial cells at the transcriptional level. The epigenetic modulator(s) of CAM transactivation and its underlying pathophysiological relevance remain poorly defined. Our goal was to determine the involvement of Brg1 and Brm in CAM transactivation and its relevance in the pathogenesis of atherosclerosis. In the present study, we report that pro-inflammatory stimuli augmented the expression of Brg1 and Brm in vitro in cultured endothelial cells and in vivo in arteries isolated from rodents. Over-expression of Brg1 and Brm promoted whereas knockdown of Brg1 and Brm abrogated transactivation of adhesion molecules and leukocyte adhesion induced by inflammatory signals. Brg1 and Brm interacted with and were recruited to the CAM promoters by NF-κB/p65. Conversely, depletion of Brg1 and Brm disrupted the kinetics of p65 binding on CAM promoters and crippled CAM activation. Silencing of Brg1 and Brm also altered key epigenetic changes associated with CAM transactivation. Of intrigue, 17β-estradiol antagonized both the expression and activity of Brg1/Brm. Most importantly, endothelial-targeted elimination of Brg1/Brm conferred atheroprotective effects to Apoe−/− mice on a Western diet. Therefore, our data suggest that Brg1 and Brm integrate various pro-inflammatory cues into CAM transactivation and endothelial malfunction and as such may serve as potential therapeutic targets in treating inflammation related cardiovascular diseases.