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Notch1-mediated inflammation is associated with endothelial dysfunction in human brain microvascular endothelial cells upon particulate matter exposure

Abstract

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 PM10 exposure (up to 25 μg/mL) increase Notch1 cleavage, and it regulates endothelial dysfunction through NICD-mediated inflammation and senescence. PM10-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 PM10-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.

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Funding

This study was supported by funds (2017-NI62002-00) and (2020-NI-024-00) from Research of Korea Centers for Disease Control and Prevention to Dr. Y.H. Koh.

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PJH performed the experiments and wrote the manuscript, CJY, LHK and JC discussed and interpreted the findings. KYH supervised the project and revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Young Ho Koh.

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Park, J.H., Choi, JY., Lee, HK. et al. Notch1-mediated inflammation is associated with endothelial dysfunction in human brain microvascular endothelial cells upon particulate matter exposure. Arch Toxicol 95, 529–540 (2021). https://doi.org/10.1007/s00204-020-02942-9

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