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

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.

PARP-1: a new player in the asthma field?

“…Therefore, PARP-1 mediated PARylation can contribute to either the degradation (via proteasome activation), or the stabilization of substrate proteins. Such a PARP-1 mediated stabilization was already demonstrated for HIF1a (19) or p53 (20).…”

CaMKII Inhibitor KN-62 Blunts Tumor Response to Hypoxia by Inhibiting HIF-1α in Hepatoma Cells

“…Several studies using PARP-/-MEF and PARP inhibitors showed that active PARP is required for HIF-1α expression and activation [20][21][22]. In other studies, however, PARP did not affect HIF-1α expression but functioned as a coactivator of HIF-1α [23].…”

“…Interestingly, the elevation of intracellular calcium is among the wide array of PARP-activating stimuli [18,19]. Moreover, the genetic or pharmacological inhibition of PARP1 attenuates the hypoxic induction of HIF-1α and other hypoxia-induced genes [20][21][22][23].…”

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

“…Martin-Oliva et al [60] were the firstto show that HIF-1-induced suppression of Complex II and Complex IV in deferoxamine-induced hypoxia depends on PARP-1 activation and the PARP-1-mediated production of ROS [61][62][63]. The inhibition of PARP-1 blocks HIF-1 activation and expression of HIF-dependent genes, among them the factor inhibiting HIF (FIH) [64,65].…”

“…HK dissociates from the mitochondrial surface upon Iduna-mediated PAR efflux from the nucleus [23][24][25], suggesting that PARP activation can in fact uncouple glycolysis and mitochondrial anabolism. Furthermore, HIF activation, that suppresses mitochondria and induces glycolysis (Warburgtype metabolism) and neoplastic transformation, is supported by PARP activation [60][61][62]64,66]. The interaction between the PI3K pathway and PARPs can be implicated in Warburg-type metabolic rearrangements, as PARP inhibitors and PI3K pathway inhibitors can potentiate each other's antitumor activities [75,82].…”