High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction
High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction
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DOI：
10.3390/ijms20143570
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发表时间：
2019-07-02
影响因子：
5.6
通讯作者：
Koka, Saisudha
中科院分区：
文献类型：
--
作者：
Singh, Gurinder Bir;Zhang, Yang;Koka, Saisudha
肠道微生物代谢产物氧化三甲胺（TMAO）参与心血管疾病的发病机制. TMAO诱导动脉粥样硬化和心血管疾病进展的分子机制尚不清楚。在这方面，高迁移率族蛋白1（HMGB 1），一种炎症介质，已被报道破坏细胞连接，导致血管内皮高通透性，导致内皮功能障碍。本研究测试了TMAO是否通过HMGB 1激活导致内皮功能障碍。生化和RT-PCR分析表明，TMAO以剂量依赖的方式增加内皮细胞HMGB 1的表达。然而，预先用HMGB 1结合剂Escherin处理，废除了TMAO诱导的内皮细胞中HMGB 1的产生。Western blot和免疫荧光分析显示TMAO处理的内皮细胞中细胞连接蛋白ZO-2、Occludin和VE-钙粘蛋白的表达较对照组显著降低。然而，预先用TMAO处理减弱了TMAO诱导的细胞连接蛋白的破坏。TMAO可增加内皮细胞TLR 4的表达。通过TLR 4 siRNA抑制TLR 4表达保护内皮细胞免受TMAO相关的紧密连接蛋白通过HMGB 1破坏。总之，我们的研究结果表明，HMGB 1是TMAO诱导的内皮功能障碍的重要介质之一。
The intestinal microbe -derived metabolite trimethylamine N -oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs' progression are still unclear. In this regard, high -mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to disrupt cell cell junctions, resulting in vascular endothelial hyper permeability leading to endothelial dysfunction. The present study tested whether TMAO associated endothelial dysfunction results via HMGB1 activation. Biochemical and RT-PCR analysis showed that TMAO increased the HMGB1 expression in a dose -dependent manner in endothelial cells. However, prior treatment with glycyrrhizin, an HMGB1 binder, abolished the TMAO-induced HMGB1 production in endothelial cells. Furthermore, Western blot and immunofluorescent analysis showed significant decrease in the expression of cell cell junction proteins ZO-2, Occludin, and VE-cadherin in TMAO treated endothelial cells compared with control cells. However, prior treatment with glycyrrhizin attenuated the TMAO-induced cell cell junction proteins' disruption. TMAO increased toll -like receptor 4 (TLR4) expression in endothelial cells. Inhibition of TLR4 expression by TLR4 siRNA protected the endothelial cells from TMAO associated tight junction protein disruption via HMGB1. In conclusion, our results demonstrate that HMGB1 is one of the important mediators of TMAO-induced endothelial dysfunction.