The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-κB and MAPK activation
The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-κB and MAPK activation
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溴结构域和末端外结构域的抑制通过阻断 NF-kappa B 和 MAPK 激活来抑制血管炎症
DOI：
10.1111/bph.13657
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发表时间：
2017-01-01
影响因子：
7.3
通讯作者：
Xu, Hanshi
中科院分区：
文献类型：
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作者：
Huang, Mingcheng;Zeng, Shan;Xu, Hanshi
背景与目的越来越多的证据表明，溴结构域和末端外结构域(BET)蛋白在免疫和炎症反应的调节中发挥重要作用，但它们在血管炎症中的作用尚未阐明。在这项研究中，我们研究了抑制BET溴域对血管炎症的影响和潜在的机制。从新鲜的脐带分离出实验的APPROACHUVEC。用BET溴域特异性抑制剂JQ1和Brd shRNA研究BET蛋白在血管炎症中的调节作用。用粘附法测定白细胞与HUVEC的粘附率。用Western印迹或免疫组织化学方法检测蛋白表达。用实时荧光定量聚合酶链式反应(Real-Time-PCR)检测基因表达。KEY RESULTSBET溴域抑制抑制肿瘤坏死因子-α和脂多糖诱导的黏附分子ICAM-1、VCAM-1和E-选择素的表达，并抑制白细胞与活化的HUVEC单层的黏附。JQ1还可减轻内毒素诱导的急性肺炎症模型中白细胞聚集和内皮细胞黏附分子的表达。此外，BET溴域抑制可降低肿瘤坏死因子-α刺激的人脐静脉内皮细胞p38、JNK MAPKs和核因子-kappaB的活性。P38(SB203580)或JNK(SP600125)抑制剂也可阻断肿瘤坏死因子-α诱导的核因子-kappaB的活化。靶向内皮BET溴域的策略可能为控制炎症相关疾病提供一种新的治疗方法。
BACKGROUND AND PURPOSEThere is increasing evidence indicating that bromodomain and extra-terminal domain (BET) proteins play a critical role in the regulation of immune and inflammatory responses; however, their contribution to vascular inflammation has not yet been elucidated. In this study, we investigated the effect of inhibiting BET bromodomain on vascular inflammation and the underlying mechanisms.EXPERIMENTAL APPROACHHUVECs were isolated from fresh umbilical cords. JQ1, a specific BET bromodomain inhibitor, and Brd shRNA were used to evaluate the regulation of the BET proteins in vascular inflammation. Leukocyte adhesion to HUVECs was measure by an adhesion assay. Western blot or immunohistochemical analysis was used to detect the protein expression. Real-time PCR was used to evaluate mRNA expression. Leukocyte accumulation in vivo was determined by an acute lung inflammation model.KEY RESULTSBET bromodomain inhibition suppressed the expression of adhesion molecules induced by TNF-alpha- or LPS, including ICAM-1, VCAM-1 and E-selectin, and inhibited leukocyte adhesion to activated HUVEC monolayers. Treatment with JQ1 also attenuated the LPS-induced accumulation of leukocytes and expression of endothelial adhesion molecules in the acute lung inflammation model in vivo. Furthermore, BET bromodomain inhibition reduced the activity of p38 and JNK MAPKs and NF-kappa B in TNF-alpha-stimulated HUVECs. TNF-alpha-induced NF-kappa B activation was also blocked by inhibitors of p38 (SB203580) or JNK (SP600125).CONCLUSIONS AND IMPLICATIONSBET bromodomain is important for regulating endothelial inflammation. Strategies targeting endothelial BET bromodomain may provide a new therapeutic approach for controlling inflammatory-related diseases.