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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:96.)
© 2005 American Heart Association, Inc.

Vascular Biology

Loss of Redox Factor 1 Decreases NF-B 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

From Lillehei Heart Institute (Z.G., Q.L., A.M., E.K., J.L.H.), Division of Cardiology, Department of Medicine, the Division of Oral Surgery (D.B.), School of Dentistry, and Shanghai Institute for Biological Science (Y.-F.X.), Chinese Academy of Sciences, Shanghai, China; and the Division of Hematology (J.G.), Department of Medicine, University of Minnesota, Minneapolis, Minn.

Correspondence to Jennifer L. Hall, PhD, Lillehei Heart Institute, University of Minnesota, 420 Delaware Street, Minneapolis, MN 55455. E-mail jlhall{at}umn.edu

Objective— The aim of this project was to test the hypothesis that redox factor 1 (Ref-1) was a critical upstream determinant of NF-B–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-B DNA binding activity. The NF-B–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-B 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-B activity.

Conclusions— These findings establish a role for Ref-1 as an upstream determinant of NF-B and A20-dependent signaling and endothelial survival in the vessel wall.

We assessed the role of Ref-1 as an upstream determinant governing NF-B survival pathways in the vessel. NF-B binding and A20 were downregulated in aortas of Ref-1+/– mice. Further studies defined the region(s) of Ref-1 regulating NF-B and survival.

Key Words: redox factor 1 • endothelial • NF-B • A20 • apoptosis • signal transduction • vascular biology • endothelium

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