Nitric oxide modulates hypoxia-inducible factor-1 and poly(ADP-ribose) polymerase-1 cross talk in response to hypobaric hypoxia

Abstract

The physiological response to hypobaric hypoxia represents a complex network of biochemical pathways in which the nitrergic system plays an important role. Previous studies have provided evidence for an interplay between the hypoxia-inducible factor-1 (HIF-1) and poly(ADP-ribose) polymerase-1 (PARP-1) under hypoxia. Here, we evaluate the potential involvement of nitric oxide (NO) in the cross talk between these two proteins. With this aim, we studied comparatively the effect of pharmacological inhibitors of NO production or PARP activity in the response of the mouse cerebral cortex to 4 h of exposure to a simulated altitude of 31,000 ft. Particularly, we analyzed the NO and reactive oxygen species production, the expression of NO synthase (NOS) isoforms, PARP-1 activity, HIF-1α expression and HIF-1 transcriptional activity, the protein level of the factor inhibiting HIF, and, finally, beclin-1 and fractin expression, as markers of cellular damage. Our results demonstrate that the reduction of NO level did not affect reactive oxygen species production but significantly 1) dampened the posthypoxic increase in neuronal NOS and inducible NOS expression without altering endothelial NOS protein level; 2) prevented PARP activation; 3) decreased HIF-1α response to hypoxia; 4) achieved a higher long-term HIF-1 transcriptional activity by reducing factor inhibiting HIF expression; and 5) reduced hypoxic damage. The pharmacological inhibition of PARP reproduced the NOS expression pattern and the HIF-1α response observed in NOS-inhibited mice, supporting its involvement in the NO-dependent regulation of hypoxia. As a whole, these results provide new data about the molecular mechanism underlying the beneficial effects of controlling NO production under hypobaric hypoxic conditions.

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].…”

Nitric Oxide Synthase Activity Correlates with OGG1 in Ozone-Induced Lung Injury Animal Models

“…However, the mechanism remains unclear. A report showed that the reduction of NO level and NOS expression prevented (ADP-Ribose) Polymerase 1 (PARP-1) activation (Martínez-Romero et al, 2012). PARP-1 is the key factor to induce the activation of BER (Dziaman et al, 2014).…”

Cardioprotective activity of placental growth factor combined with oral supplementation of L-arginine in a rat model of acute myocardial infarction

“…The possible mechanism might be associated with the fact that PlGF depends heavily on the release of endothelial-derived NO,3 and l -arginine improves endothelial function by ameliorating the expression of eNOS and NO, ultimately enhancing myocardial tissue perfusion. Another option could be that l -arginine can also reduce endothelial cell damage under hypoxic conditions, so as to maintain the stability of new blood vessels 9. The last but not the least, possibility might be that the level of asymmetric dimethylarginine, an arginine analog that competes with l -arginine for eNOS, is increased in AMI and can also lead to the impairment of endothelial function, and the competitive inhibition of eNOS by asymmetric dimethylarginine may be reversed by the supplementation of l -arginine 25…”

“…Since l -arginine is a substrate for eNOS, its supplementation in animals improves endothelial function 8. This amino acid can also diminish the endothelial cell damage caused by various factors under hypoxic conditions and stimulate angiogenesis 9. However, the therapeutic effects of intramyocardial injection of PlGF combined with oral supplementation of l -arginine have not been investigated.…”