Abstract:
:We hypothesized that a redox-sensitive transcription factor, redox factor-1 (Ref-1) (HAP1, APE, and APEX), was critical in the regulation of endothelial cell survival in response to hypoxia and cytokines, including tumor necrosis factor (TNF)-alpha. Hypoxia resulted in a significant decrease in Ref-1 protein expression in both human umbilical vein endothelial cells and calf pulmonary artery endothelial cells. The hypoxia-induced decrease in Ref-1 expression was followed by a significant induction of apoptosis as measured by caspase 3 activity and nuclear morphology. Transient upregulation of Ref-1 significantly inhibited hypoxia-induced apoptosis. However, deletion of the redox-sensitive domain of Ref-1 abolished the antiapoptotic effect. We postulated that the antiapoptotic effects of Ref-1 were mediated through nuclear factor-kappaB (NF-kappaB). However, blockade of NF-kappaB with a dominant-negative IkappaB (S32A/S36A) expression vector had no effect on Ref-1-mediated survival under hypoxic conditions. The second aim of this study was to test the cytoprotective ability of Ref-1 upregulation in response to TNF-induced apoptosis. Ref-1 inhibition of TNF-induced death was associated with a significant potentiation of NF-kappaB activity. Deletion of the redox-sensitive domain of Ref-1 significantly inhibited TNF-induced NF-kappaB activation. Moreover, loss of the redox-sensitive domain also abolished the antiapoptotic effect of Ref-1 in response to TNF. To test whether Ref-1 induced activation of NF-kappaB was necessary to promote survival, we blocked NF-kappaB activity with a dominant-negative IkappaB (S32A/S36A). Indeed, blockade of NF-kappaB activity abolished the ability of Ref-1 to rescue TNF-induced apoptosis. In conclusion, upregulation of Ref-1 promotes endothelial cell survival in response to hypoxia and TNF through NF-kappaB-independent and NF-kappaB-dependent signaling cascades, respectively. Moreover, it seems that Ref-1 may act as a critical cofactor, mediating the TNF-induced NF-kappaB response in the vascular endothelium.
journal_name
Circ Resjournal_title
Circulation researchauthors
Hall JL,Wang X,Van Adamson,Zhao Y,Gibbons GHdoi
10.1161/hh1201.091796subject
Has Abstractpub_date
2001-06-22 00:00:00pages
1247-53issue
12eissn
0009-7330issn
1524-4571journal_volume
88pub_type
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