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Published on: January 7, 2019
Notch Signaling Pathway Regulates Ozone-Induced Lung Circadian Rhythm Disruption
Xinyu Zhang1,2, Xiaotong Jian2, Xinyi Miao2
1Henan Clinical Research Center of Childhood Diseases, Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China.
Background:
Ozone (O3) pollution disrupts pulmonary circadian rhythms, yet the molecular mechanisms remain elusive. The Notch signaling pathway, critical for lung homeostasis, may crosstalk with the circadian clock system.
Objective:
This study elucidates the role of the Notch signaling pathway in O3-induced lung circadian rhythm disruption.
Methods:
C57BL/6J mice were acutely exposed to O3 (1.0 ppm, 3 h). Lung tissues were collected 24 h post exposure. Transcriptome sequencing coupled with GSEA identified dysregulated pathways; IHC and RT-qPCR validated core genes; GEO dataset (GSE58244) reanalysis assessed Notch3/4 knockout effects.
Results:
O3 activated Notch signaling (NES = 1.85, FDR = 0.034) and disrupted the circadian pathway (NES = 1.84, FDR = 0.029), downregulating Bmal1 while upregulating Per2/3 and Notch3/4 (p < 0.05). Strong correlations (r > 0.8) existed between core genes of both pathways. Notch3/4 knockout exacerbated circadian disruption in a time-dependent manner upon O3 exposure.
Conclusion:
O3 induces lung circadian disruption via Notch3/4 activation, which provides novel mechanistic insights into pollutant-induced lung injury.
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