PARP‐1 modulates deferoxamine‐induced HIF‐1α accumulation through the regulation of nitric oxide and oxidative stress

Publisher Website
Google Scholar
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 α subunit which is regulated, in part, by oxidative stress (ROS) and nitric oxide (NO), both of them highly dependent on PARP‐1. Besides, HIF‐1α 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‐1α accumulation induced by treatment with DFO. Our results show that, in DFO treated cells, PARP‐1 gene deletion or inhibition decreases HIF‐1α accumulation. This lower HIF‐1α 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. J. Cell. Biochem. 104: 2248–2260, 2008.

This publication has 64 references indexed in Scilit: