Ref-1 and transcriptional control of endothelial apoptosis.

Abstract

Vascular endothelium, when unperturbed, provides a surface to the blood vessel, which is passive to the development of thrombosis, and potentially adherent blood cells. This characteristic is the quintessence of vascular homeostasis.1 However, endothelial cells (ECs) can undergo apoptosis in vitro in response to a variety of pathophysiological conditions including hypoxia, proinflammatory cytokines, bacterial endotoxins, and atherogenic risk factors such as homocysteine and lipoproteins (reviewed in Stefanec2 and Dimmeler and Zeiher3 ). These cellular perturbations have in common the generation of intracellular reactive oxygen intermediates, referred to as oxidative stress. ECs respond to these adverse conditions by altering their intracellular reduction/oxidization (redox) state and making their ultimate decision between adaptation (survival) and apoptosis (see Figure⇓). Understanding the precise mechanisms controlling such a process is an important component to our knowledge of cardiovascular diseases. In this issue of Circulation Research , Hall et al4 provide novel evidence for a critical role of Ref-1, a redox-sensitive regulator, in affecting EC apoptosis. Ref-1 was cloned as Redox factor, also known as apurinic (apyrimidinic) endonuclease (APE).5 As a ubiquitously expressed multifunctional 36-kDa protein, Ref-1 is involved in the repair of DNA damage as well as in the transcriptional regulation of genes. Its 5′AP-endonuclease functions in base excision repair, and its 3′-diesterase activity removes phosphoglycolate residues from DNA damaged by genotoxic stresses. In addition, Ref-1 is also important for the activation of transcription factors, such as activator protein-1 (AP-1),6 7 nuclear factor-κB (NF-κB),8 p53,9 10 and hypoxia-inducible factor-1α (HIF-1α).11 Activation of transcription factors, which occurs via a redox-based mechanism, pertains to its 6-kDa N-terminal domain. Following its discovery, Xanthoudakis and Curran12 identified Ref-1 as a reductive activator of c-Fos and c-Jun (two major components of AP-1) via a reduction of the conserved cysteine residues …