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Focal TLR4 activation mediates disturbed flow-induced endothelial inflammation.
Cardiovascular Research ( IF 10.2 ) Pub Date : 2020-01-01 , DOI: 10.1093/cvr/cvz046
Dan Qu,Li Wang,Mingyu Huo,Wencong Song,Chi-Wai Lau,Jian Xu,Aimin Xu,Xiaoqiang Yao,Jeng-Jiann Chiu,Xiao Yu Tian,Yu Huang

AIMS Disturbed blood flow at arterial branches and curvatures modulates endothelial function and predisposes the region to endothelial inflammation and subsequent development of atherosclerotic lesions. Activation of the endothelial Toll-like receptors (TLRs), in particular TLR4, contributes to vascular inflammation. Therefore, we investigate whether TLR4 can sense disturbed flow (DF) to mediate the subsequent endothelial inflammation. METHODS AND RESULTS En face staining of endothelium revealed that TLR4 expression, activation, and its downstream inflammatory markers were elevated in mouse aortic arch compared with thoracic aorta, which were absent in Tlr4mut mice. Similar results were observed in the partial carotid ligation model where TLR4 signalling was activated in response to ligation-induced flow disturbance in mouse carotid arteries, and such effect was attenuated in Tlr4mut mice. DF in vitro increased TLR4 expression and activation in human endothelial cells (ECs) and promoted monocyte-EC adhesion, which were inhibited in TLR4-knockdown ECs. Among endogenous TLR4 ligands examined as candidate mediators of DF-induced TLR4 activation, fibronectin containing the extra domain A (FN-EDA) expressed by ECs was increased by DF and was revealed to directly interact with and activate TLR4. CONCLUSION Our findings demonstrate the indispensable role of TLR4 in DF-induced endothelial inflammation and pinpoint FN-EDA as the endogenous TLR4 activator in this scenario. This novel mechanism of vascular inflammation under DF condition may serve as a critical initiating step in atherogenesis.

中文翻译:

局灶性TLR4激活介导了紊乱的血流诱导的内皮炎症。

目的动脉分支和曲率处的血流紊乱可调节内皮功能,并使该区域易于发生内皮炎症和动脉粥样硬化病变的发展。内皮Toll样受体(TLR),特别是TLR4的激活有助于血管炎症。因此,我们调查了TLR4是否可以感知扰动的血流(DF)来介导随后的内皮炎症。方法和结果内皮全脸染色显示,与Tlr4mut小鼠中没有的胸主动脉相比,小鼠主动脉弓中TLR4的表达,激活及其下游炎症标志物升高。在部分颈动脉结扎模型中观察到了相似的结果,在该模型中,响应结扎诱导的小鼠颈动脉血流紊乱,激活了TLR4信号传导,在Tlr4mut小鼠中这种作用减弱了。DF体外提高了人内皮细胞(EC)中TLR4的表达和激活,并促进了单核细胞与EC的粘附,这在TLR4抑制型EC中受到抑制。在作为DF诱导的TLR4激活的候选介体而检查的内源性TLR4配体中,由EC所表达的含有ECs表达的额外结构域A(FN-EDA)的纤连蛋白被DF增强,并被发现与TLR4直接相互作用并激活TLR4。结论我们的研究结果表明,在这种情况下,TLR4在DF诱导的内皮炎症中起着不可或缺的作用,并确定了FN-EDA作为内源性TLR4激活剂。DF条件下这种血管炎症的新机制可能是动脉粥样硬化形成过程中的关键启动步骤。DF体外提高了人内皮细胞(EC)中TLR4的表达和激活,并促进了单核细胞与EC的粘附,这在TLR4抑制型EC中受到抑制。在作为DF诱导的TLR4激活的候选介体而检查的内源性TLR4配体中,由EC所表达的含有ECs表达的额外结构域A(FN-EDA)的纤连蛋白被DF增强,并被发现与TLR4直接相互作用并激活TLR4。结论我们的研究结果表明,在这种情况下,TLR4在DF诱导的内皮炎症中起着不可或缺的作用,并确定了FN-EDA作为内源性TLR4激活剂。DF条件下这种血管炎症的新机制可能是动脉粥样硬化形成过程中的关键启动步骤。DF体外提高了人内皮细胞(EC)中TLR4的表达和激活,并促进了单核细胞与EC的粘附,这在TLR4-nockdown EC中受到抑制。在作为DF诱导的TLR4活化的候选介体而检查的内源性TLR4配体中,由EC所表达的含有ECs表达的额外结构域A(FN-EDA)的纤连蛋白被DF增强,并被发现与TLR4直接相互作用并激活TLR4。结论我们的研究结果表明,在这种情况下,TLR4在DF诱导的内皮炎症中起着不可或缺的作用,并确定了FN-EDA作为内源性TLR4激活剂。DF条件下这种血管炎症的新机制可能是动脉粥样硬化形成过程中的关键启动步骤。在作为DF诱导的TLR4激活的候选介体而检查的内源性TLR4配体中,由EC所表达的含有ECs表达的额外结构域A(FN-EDA)的纤连蛋白被DF增强,并被发现与TLR4直接相互作用并激活TLR4。结论我们的研究结果表明,在这种情况下,TLR4在DF诱导的内皮炎症中起着不可或缺的作用,并确定了FN-EDA作为内源性TLR4激活剂。DF条件下这种血管炎症的新机制可能是动脉粥样硬化形成过程中的关键启动步骤。在作为DF诱导的TLR4活化的候选介体而检查的内源性TLR4配体中,由EC所表达的含有ECs表达的额外结构域A(FN-EDA)的纤连蛋白被DF增强,并被发现与TLR4直接相互作用并激活TLR4。结论我们的研究结果表明,在这种情况下,TLR4在DF诱导的内皮炎症中起着不可或缺的作用,并确定了FN-EDA作为内源性TLR4激活剂。DF条件下这种血管炎症的新机制可能是动脉粥样硬化形成过程中的关键启动步骤。结论我们的研究结果表明,在这种情况下,TLR4在DF诱导的内皮炎症中起着不可或缺的作用,并确定了FN-EDA作为内源性TLR4激活剂。DF条件下这种血管炎症的新机制可能是动脉粥样硬化形成过程中的关键启动步骤。结论我们的研究结果表明,在这种情况下,TLR4在DF诱导的内皮炎症中起着不可或缺的作用,并确定了FN-EDA作为内源性TLR4激活剂。DF条件下这种血管炎症的新机制可能是动脉粥样硬化形成过程中的关键启动步骤。
更新日期:2019-12-19
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