Division of Brain Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, 28159, Republic of Korea.
Arch Toxicol. 2021 Feb;95(2):529-540. doi: 10.1007/s00204-020-02942-9. Epub 2020 Nov 7.
Exposure to atmospheric particulate matter (PM) is an emerging risk factor for the pathogenesis of several diseases in humans, including cerebrovascular diseases. However, the mechanisms underlying PM-induced endothelial dysfunction are currently unclear. In this study, we examined how PM leads to endothelial dysfunction in human brain microvascular endothelial cells (HBMECs). We demonstrated that PM exposure (up to 25 μg/mL) increase Notch1 cleavage, and it regulates endothelial dysfunction through NICD-mediated inflammation and senescence. PM-induced NICD signaling causes increased expression of interleukin-1 beta (IL-1β) and enhances characteristics of cellular senescence, which leads to increased endothelial permeability in HBMECs. Knockdown of Notch1 by siRNA blocks PM-induced endothelial dysfunction via the suppression of inflammation and senescence. Furthermore, we found that Notch1-mediated inflammation accelerates endothelial senescence, which eventually leads to endothelial dysfunction. Altogether, our data suggest that Notch1 and NICD are potential target regulators for the prevention of cerebrovascular endothelial dysfunction induced by ambient air pollutants such as PM.
大气颗粒物 (PM) 的暴露是人类几种疾病发病机制的一个新出现的危险因素，包括脑血管疾病。然而，目前尚不清楚 PM 诱导内皮功能障碍的机制。在这项研究中，我们研究了 PM 如何导致人脑血管内皮细胞 (HBMEC) 的内皮功能障碍。我们证明，PM 暴露（高达 25μg/ml）增加 Notch1 切割，并且它通过 NICD 介导的炎症和衰老来调节内皮功能障碍。PM 诱导的 NICD 信号导致白细胞介素 1β（IL-1β）的表达增加，并增强细胞衰老的特征，导致 HBMEC 中内皮通透性增加。通过 siRNA 敲低 Notch1 通过抑制炎症和衰老来阻断 PM 诱导的内皮功能障碍。此外，我们发现 Notch1 介导的炎症加速内皮衰老，最终导致内皮功能障碍。总之，我们的数据表明，Notch1 和 NICD 是预防大气污染物（如 PM）引起的脑血管内皮功能障碍的潜在靶调节因子。
