Redox factor-1: an extra-nuclear role in the regulation of endothelial oxidative stress and apoptosis

Abstract

The rac1 GTPase promotes oxidative stress through reactive oxygen species (ROS) production, whereas the DNA repair enzyme and transcriptional regulator redox factor-1 (ref-1) protects against cell death due to oxidative stimuli. However, the function of ref-1 in regulating intracellular oxidative stress, particularly that induced by rac1, has not been defined. We production), NF-k kB activation, and apoptosis, and also mitigated rac1-regulated H 2 O 2 production and NF-k kB transcriptional activity. We conclude that inhibition of oxidative stress is another mechanism by which ref-1 protects against apoptosis, and that this is achieved through modulation of cytoplasmic rac1-regulated ROS generation. This suggests a novel extra-nuclear function of ref-1.

Cytoplasmic Localization and Redox Cysteine Residue of APE1/Ref-1 Are Associated with Its Anti-Inflammatory Activity in Cultured Endothelial Cells

“…The subcellular distribution of APE1/Ref-1 may be regulated by both nuclear import and export systems (Jackson et al, 2005). APE1/Ref-1 undergoes active shuttling between the cytoplasm and nucleus in response to oxidative (Angkeow et al, 2002;Bhakat et al, 2003;Tell et al, 2000a) and nitrosative stress (Qu et al, 2007). In endothelial cells, the translocation of APE1/Ref-1 into the cytoplasm has been previously reported.…”

“…Furthermore, extra-nuclear functions of APE1/Ref-1 have been revealed (Jeon and Irani, 2009). APE1/Ref-1 reduces intracellular ROS production via inhibition of Rac1 activation in NADPH oxidase (Angkeow et al, 2002;Guo et al, 2008;Ozaki et al, 2002). It is well known that mitogen-activated protein kinase (MAPK)s are activated by growth factors, environmental stresses and inflammatory cytokine (Chen et al, 2001).…”

“…It is well known that mitogen-activated protein kinase (MAPK)s are activated by growth factors, environmental stresses and inflammatory cytokine (Chen et al, 2001). We previously reported that the overexpression of APE1/Ref-1 using the adenoviral gene transfer system inhibits TNF-α-induced ROS production and VCAM-1 in endothelial cells (Angkeow et al, 2002;Kim et al, 2006;Lee et al, 2009). In addition, p38 MAPK activation by TNF-α was blocked by overexpression of APE1/Ref-1 resulting in inhibition of TNF-α-induced VCAM-1 in endothelial cell .…”

“…APE1/Ref-1 suppresses oxidative stress through modulation of cytoplasmic Rac1-regulated generation of reactive oxygen species (Angkeow et al, 2002;Ozaki et al, 2002) and stimulates nitric oxide production by activating endothelial nitric oxide synthase (Jeon et al, 2004). In endothelial cells, APE1/Ref-1 mitigates TNF-α-induced monocyte adhesion and suppresses the expression of vascular cell adhesion molecules .…”

Overexpression of Ref-1 Inhibits Lead-induced Endothelial Cell Death via the Upregulation of Catalase

“…Additionally, Ref-1 is a critical factor in cellular protection against cell death resulting from oxidative stresses, including endothelial cell activation and inflammation. Ref-1 has also been shown to suppress intracellular oxidative stress and apoptosis (Angkeow et al, 2002;Ozaki et al, 2002;Yoo et al, 2004). It was recently reported that vascular endothelial cell activation and vascular inflammation were inhibited by Ref-1 overexpression (Kim et al, 2006;Song et al, 2008;Lee et al, 2009).…”