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ZFIN ID: ZDB-PUB-171019-25
Ultrafine Particles Exposure Reveals the Importance of FOXO1/Notch Activation Complex for Vascular Regeneration
Baek, K.I., Packard, R.R., Hsu, J.J., Saffari, A., Ma, Z., Luu, A.P., Pietersen, A., Yen, H., Ren, B., Ding, Y., Sioutas, C., Li, R., Hsiai, T.K.
Date: 2017
Source: Antioxidants & redox signaling   28(13): 1209-1223 (Journal)
Registered Authors: Baek, Kyung
Keywords: none
MeSH Terms:
  • Animals
  • Cells, Cultured
  • Endothelial Cells/drug effects*
  • Endothelial Cells/metabolism
  • Forkhead Box Protein O1/metabolism*
  • Oxidation-Reduction
  • Particulate Matter/administration & dosage
  • Particulate Matter/pharmacology*
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Receptors, Notch/metabolism*
  • Regeneration/drug effects*
  • Zebrafish
  • Zebrafish Proteins/metabolism*
PubMed: 29037123 Full text @ Antioxid. Redox Signal.
Redox active ultrafine particles (UFP, d < 0.2 ┬Ám) promote vascular oxidative stress and atherosclerosis. Notch signaling is intimately involved in vascular homeostasis, in which FOXO1 acts a co-activator of the Notch activation complex. We elucidated the importance of FOXO1/Notch transcriptional activation complex to restore vascular regeneration following UFP exposure.
In a zebrafish model of tail injury and repair, transgenic Tg(fli1:GFP) embryos developed vascular regeneration at 3 days post tail amputation, whereas UFP exposure impaired regeneration (P < 0.05, n = 20 for control, n = 28 for UFP). UFP dose-dependently reduced Notch reporter activity and Notch signaling-related genes (Dll4, JAG1, JAG2, Notch1b, Hey2, Hes1) (P < 0.05, n = 3). In the transgenic Tg(tp1:GFP; flk1:mCherry) embryos, UFP attenuated endothelial Notch activity at the amputation site (P < 0.05, n = 20). ADAM10 inhibitor or dominant negative (DN)-Notch1b mRNA disrupted, whereas Notch Intracellular Cytoplasmic Domain (NICD) mRNA restored vascular network (P < 0.05, n = 20). UFP reduced FOXO1 expression, but not Master-mind like 1 (MAML1) or NICD (P < 0.05, n = 3). Immunoprecipitation and immunofluorescence demonstrated that UFP attenuated FOXO1-mediated NICD pull-down and FOXO1/NICD co-localization, respectively (P < 0.05, n = 3). While FOXO1 morpholino oligonucleotides attenuated Notch activity, FOXO1 mRNA reversed UFP-mediated reduction in Notch activity to restore vascular regeneration and blood flow (P < 0.05 , n = 5). Innovation and Conclusion: Our findings indicate the importance of FOXO1/Notch activation complex to restore vascular regeneration following exposure to the redox active UFP.