PARP-1 modulates deferoxamine-induced HIF-1alpha accumulation through the regulation of nitric oxide and oxidative stress.
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.
Martínez-Romero
Rubén
R
Department of Experimental Biology, University of Jaén, Paraje Las Lagunillas s/n, 23071-Jaén, Spain.
Martínez-Lara
Esther
E
Aguilar-Quesada
Rocío
R
Peralta
Andreína
A
Oliver
F Javier
FJ
Siles
Eva
E
D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D003676:Deferoxamine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors
D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053607:Adrenomedullin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases; D003676:Deferoxamine