Loss of redox factor 1 decreases NF-κB activity and increases susceptibility of endothelial cells to apoptosis

Zhanjun Guan, David Basi, Qinglu Li, Ami Mariash, Yi Feng Xia, Jian Guo Geng, Esther Kao, Jennifer L. Hall

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Objective - The aim of this project was to test the hypothesis that redox factor 1 (Ref-1) was a critical upstream determinant of NF-κB-dependent survival signaling pathways in the vessel wall. Methods and Results - Aortas from hemizygous transgenic mice harboring a single allele of Ref-1 exhibited a significant loss in NF-κB DNA binding activity. The NF-κB-dependent survival gene A20 was significantly downregulated in aortas of hemizygous Ref-1 mice, whereas IAP-2 was unchanged. Overexpression of A20 rescued cells from tumor necrosis factor (TNF)-induced apoptosis, suggesting that the loss of A20 in Ref-1 hemizygotes may be a rate-determining step in endothelial cell fate. Deletion of the previously defined redox-sensitive or the AP endonuclease domains of Ref-1 significantly decreased NF-κB transcriptional activation and endothelial cell survival. Furthermore, TNF-induced apoptosis was significantly potentiated in endothelial cells after delivery of Morpholino antisense oligodeoxynucleotides targeted to Ref-1. Loss of the redox-sensitive domain blocked the ability of Ref-1 to reduce p50; however, loss of the endonuclease domain did not effect p50 reduction, suggesting alternative mechanisms of action of Ref-1 on NF-κB activity. Conclusions - These findings establish a role for Ref-1 as an upstream determinant of NF-κB and A20-dependent signaling and endothelial survival in the vessel wall.

Original languageEnglish (US)
Pages (from-to)96-101
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume25
Issue number1
DOIs
StatePublished - Jan 2005

Keywords

  • A20
  • Apoptosis
  • Endothelial
  • Endothelium
  • NF-κB
  • Redox factor 1
  • Signal transduction
  • Vascular biology

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