IRE1α/XBP1s branch of UPR links HIF1α activation to mediate ANGII-dependent endothelial dysfunction under particulate matter (PM) 2.5 exposure.
IRE1α/XBP1s branch of UPR links HIF1α activation to mediate ANGII-dependent endothelial dysfunction under particulate matter (PM) 2.5 exposure.
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DOI：
10.1038/s41598-017-13156-y
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发表时间：
2017-10-18
影响因子：
4.6
通讯作者：
Song L
中科院分区：
文献类型：
--
作者：
Xu X;Qimuge A;Wang H;Xing C;Gu Y;Liu S;Xu H;Hu M;Song L
短期和长期暴露于颗粒物（PM）2.5会对心血管（CV）系统产生不良健康影响。揭示PM2.5引起CV损伤的分子事件对于制定有效的降低风险策略至关重要。在这里，我们发现，大鼠气管内滴注PM2.5后，血管紧张素II（RAS中的主要生物活性肽）的循环水平增加，这是由于血管内皮中血管紧张素II的产生增加所致。进一步的研究表明，未折叠蛋白反应（unfolded protein response，UPR）的IRE 1 α/XBP 1 s分支的激活是PM2.5暴露后血管ANGII信号增强的关键，其作用严格依赖于XBP 1 s/HIF 1 α转录复合物的组装。此外，阻断IRE 1/XBP 1/HIFα依赖的ACE/ANGII/AT 1 R轴激活可抑制PM2.5诱导的血管内皮细胞氧化应激和促炎反应。因此，我们得出结论，PM2.5暴露刺激内质网不稳定，导致诱导IRE 1 α/XBP 1 s分支的UPR和连接HIF 1 α反式激活介导ANGII依赖性内皮功能障碍。确定新的治疗靶点以缓解ER应激并恢复内皮中局部RAS稳态可能有助于管理PM2.5诱导的CV负担。
Short- and long-term exposure to particulate matter (PM) 2.5 instigates adverse health effect upon the cardiovascular (CV) system. Disclosing the molecular events by which PM2.5 evokes CV injuries is essential in developing effective risk-reduction strategy. Here we found that rats after intratracheally instillation with PM2.5 displayed increased circulating level of ANGII, the major bioactive peptide in renin-angiotensin-system (RAS), which resulted from the elevation of ANGII production in the vascular endothelium. Further investigations demonstrated that activation of IRE1α/XBP1s branch of unfolded protein response (UPR) was essential for augmented vascular ANGII signaling in response to PM2.5 exposure, whose effects strictly depends on the assembly of XBP1s/HIF1α transcriptional complex. Moreover, ablation of IRE1/XBP1/HIFα-dependent ACE/ANGII/AT1R axis activation inhibited oxidative stress and proinflammatory response in the vascular endothelial cells induced by PM2.5. Therefore, we conclude that PM2.5 exposure instigates endoplasmic reticulum instability, leading to the induction of IRE1α/XBP1s branch of UPR and links HIF1α transactivation to mediate ANGII-dependent endothelial dysfunction. Identifying novel therapeutic targets to alleviate ER stress and restore local RAS homeostasis in the endothelium may be helpful for the management of PM2.5-induced CV burden.
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DOI：
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发表时间：
2012-10-01
期刊：
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影响因子：
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发表时间：
2009-04
期刊：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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