MAPK/AP-1 pathway activation mediates AT1R upregulation and vascular endothelial cells dysfunction under PM2.5 exposure
MAPK/AP-1 pathway activation mediates AT1R upregulation and vascular endothelial cells dysfunction under PM2.5 exposure
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PM2.5暴露下MAPK/AP-1通路激活介导AT1R上调和血管内皮细胞功能障碍
DOI：
10.1016/j.ecoenv.2018.11.124
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发表时间：
2019-04-15
影响因子：
6.8
通讯作者：
Song, Lun
中科院分区：
文献类型：
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作者：
Xu, Xiuduan;Xu, Huan;Song, Lun
急性和长期暴露于颗粒物(PM)2.5会对心血管系统产生不良健康影响。然而，PM2.5引起脑血管损伤的分子机制尚未完全阐明。在我们最近的报告中，我们证明暴露于PM2.5会导致循环血管紧张素II(AngII)水平升高，血管内皮细胞局部表达血管紧张素原(AngⅡ)、血管紧张素转换酶(ACE)和血管紧张素Ⅱ1型受体(AT1R)，从而引发血管内皮细胞的氧化应激和促炎反应。在本研究中，我们揭示了PM2.5暴露诱导了人血管内皮细胞转录因子AP-1及其组分c-jun和ATF2的激活。虽然AP-1的DNA结合位点位于AGT、ACE和AT1R基因的启动子区域，但RT-PCR和免疫印迹分析表明，在相同条件下，AP-1的反式激活只参与AT1R的上调，而不影响AGT和ACE的表达。此外，在PM2.5刺激下，ERKs和p38K是参与AP-1反式激活和AT1R上调的上游蛋白激酶。此外，当MAPKs和AP-1的激活被抑制时，PM2.5处理的血管内皮细胞的氧化应激和促炎反应显著减少。因此，我们得出结论，PM2.5暴露诱导MAPK/AP-1级联激活，从而导致AT1R上调和血管内皮细胞功能障碍。寻找新的治疗靶点以减轻AP-1的反式激活和恢复AT1R的表达可能有助于PM2.5诱导的心血管负荷的管理。
Acute and chronic exposure to particulate matter (PM) 2.5 is associated with adverse health effect upon the cardiovascular (CV) system. However, the molecular mechanism by which PM2.5 evokes CV injuries has not been fully clarified. In our recent report, we demonstrate that exposure to PM2.5 leads to elevation of circulating angiotensin II (ANGII) levels and local expressions of angiotensinogen (AGT, the precursor of ANGII), angiotensin-converting enzyme (ACE) and ANGII type 1 receptor (AT1R) in the vascular endothelial cells, which subsequently instigates the oxidative stress and proinflammatory response in the vascular endothelium. In the present study, we disclosed that PM2.5 exposure induced the activation of the transcriptional factor AP-1 and its components, c-Jun and ATF2, in the human vascular endothelial cells. Although the DNA-binding sites for AP-1 were identified within the promoter regions of AGT, ACE and AT1R genes, RT-PCR and immunoblot assays indicated that AP-1 transactivation was only involved in AT1R upregulation, but did not affect the induction of AGT and ACE expression under the same conditions. Furthermore, ERKs and p38K functioned as the upstream protein kinases involving in AP-1 transactivation and AT1R upregulation under PM2.5 stimulation. In addition, the oxidative stress and proinflammatory responses in the PM2.5-treated vascular endothelial cells were significantly reduced when MAPKs and AP-1 activation were inhibited. Therefore, we conclude that PM2.5 exposure induces MAPK/AP-1 cascade activation, which contributes to AT1R upregulation and vascular endothelial dysfunction. Identifying novel therapeutic targets to alleviate AP-1 transactivation and restore AT1R expression may be helpful for the management of PM2.5-induced CV burden.