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  • Title: PARP-1 modulates deferoxamine-induced HIF-1alpha accumulation through the regulation of nitric oxide and oxidative stress.
    Author: Martínez-Romero R, Martínez-Lara E, Aguilar-Quesada R, Peralta A, Oliver FJ, Siles E.
    Journal: J Cell Biochem; 2008 Aug 15; 104(6):2248-60. PubMed ID: 18459142.
    Abstract:
    Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that, once activated by genotoxic agents, modulates the activity of several nuclear proteins including itself. Previous studies have established that PARP-1 inhibition may provide benefit in the treatment of different diseases, particularly those involving a hypoxic situation, in which an increased oxidative and nitrosative stress occurs. One of the most important transcription factors involved in the response to the hypoxic situation is the hypoxia-inducible factor-1 (HIF-1). The activity of HIF-1 is determined by the accumulation of its alpha subunit which is regulated, in part, by oxidative stress (ROS) and nitric oxide (NO), both of them highly dependent on PARP-1. Besides, HIF-1alpha can be induced by iron chelators such as deferoxamine (DFO). In this sense, the therapeutical use of DFO to strengthen the post-hypoxic response has recently been proposed. Taking into account the increasing interest and potential clinical applications of PARP inhibition and DFO treatment, we have evaluated the impact of PARP-1 on HIF-1alpha accumulation induced by treatment with DFO. Our results show that, in DFO treated cells, PARP-1 gene deletion or inhibition decreases HIF-1alpha accumulation. This lower HIF-1alpha stabilization is parallel to a decreased inducible NO synthase induction and NO production, a higher response of some antioxidant enzymes (particularly glutathione peroxidase and glutathione reductase) and a lower ROS level. Taken together, these results suggest that the absence of PARP-1 modulates HIF-1 accumulation by reducing both NO and oxidative stress.
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