Human apo-lactoferrin as a physiological mimetic of hypoxia stabilizes hypoxia-inducible factor-1 alpha

Abstract

Apo-form of human lactoferrin (LF) is a potent iron chelator, this feature being similar to the iron-binding properties of a synthetic chelator desferoxamine (DFO). The latter stabilizes the principal adaptive transcriptional hypoxia-inducible factor-1 alpha (HIF-1α). Since DFO is known as a pharmacological mimetic of hypoxia it was decided to test whether apo-LF is able to perform as such. Mice either injected intraperitoneally or given per os apo-LF displayed HIF-1α in liver, lungs, heart, brain, spleen and kidneys, as judged by results of Western blotting. Similar administration of iron-saturated LF (75 mg/kg) did not bring forth such effect. Synthesis of erythropoietin and ceruloplasmin became increased in the first case, which is explained by the respective genes being targets for HIF-1α. Apo-LF, but not Fe-LF, injected intraperitoneally to hypoxia low-resistant mice 24 h before animals were subjected to normobaric hypoxia with hypercapnia caused a significant increase of life-time by 40 %. The results obtained show that, like DFO, apo-LF performs as a normoxic mimetic of hypoxia, capable of stabilizing HIF-1α. Protective features of LF and DFO and their pharmacological properties involving HIF-1α are discussed.

Intranasal Lactoferrin Enhances α-Secretase-Dependent Amyloid Precursor Protein Processing via the ERK1/2-CREB and HIF-1α Pathways in an Alzheimer’s Disease Mouse Model

“…How synaptic activity regulates α-secretase remains unclear, although studies implicate HIF-1α as a mediator governing ADAM10 activation (Barsoum et al, 2012). Recently, (Shukla et al (2015)) observed that ERK phosphorylation upregulated ADAM10 through HIF-1α activation, and Lf is also known as a normoxic mimetic of hypoxia, capable of stabilizing HIF-1α (Zakharova et al, 2012). To determine whether upregulation of the ADAM10 protein by hLf in APP/PS1 mice occurred via the same pathway, we analyzed ERK1/2, HIF-1α, and CREB in the extracts of brain tissue.…”

“…Previous studies have indicated that LfR is involved in Lf-induced activation of the ERK1/2 and CREB, these two pathways might regulate each other and co-regulate downstream functions (Ikoma-Seki et al, 2015). Moreover, it has been reported that hypoxia contributes to ADAM10 transcription via HIF-1α activation (Barsoum et al, 2011), and Lf acts as a normoxic mimetic of hypoxia capable of stabilizing HIF-1α (Zakharova et al, 2012). To further investigate the mechanism underlying Lf-mediated upregulation of ADAM10, mitigation of amyloidosis, and inflammation, we next assessed the expression of HIF-1α and VEGF protein, and the activation of ERK1/2 and CREB in the APP/PS1 mouse brains in both hLf-and vehicletreated mice.…”

“…The iron chelator deferoxame (DFO) has been shown to provide neuroprotective effects in clinical patients and animal models of AD (Crapper McLachlan et al, 1991;Guo et al, 2013), for which the mechanism may be regulation of the transcriptional activator hypoxia-inducible factor 1α (HIF-1α) (Guo et al, 2015). Lf exhibits similar chelating features as DFO (Kontoghiorghes et al, 2010;Kruzel et al, 2010) and functions as a normoxic mimetic of hypoxia capable of stabilizing HIF-1α (Zakharova et al, 2012). It is important to consider that Lf prevents some denatured/misfolded proteins from aggregating (Takase, 1998), and its multifunctional anti-prion activities have been identified (Iwamaru et al, 2008).…”

Functional link between ferroxidase activity of ceruloplasmin and protective effect of apo-lactoferrin: studying rats kept on a silver chloride diet

“…Intraperitoneal injections to mice and rats of either human or bovine LF resulted in appearance of heterologous complexes CP-LF that were rapidly eliminated from the bloodstream (Sokolov et al 2014). It was also shown that apo-LF is a physiological mimetic of hypoxia capable of stabilizing HIF-1a and increasing the expression of hypoxia-inducible target genes encoding such proteins as erythropoietin (EPO) and CP (Zakharova et al 2012). Our suggestion was that chelating capacity of apo-LF favors the inhibition of iron-dependent prolyland asparaginyl-hydroxylases (PHD and/or FIH) which normally cause destabilization of HIF-1a.…”

Potential role of lactoferrin in early diagnostics and treatment of Parkinson disease

“…Ferroxidase activity of ceruloplasmin prevents the ubiquitin-mediated degradation of ferroportin [64]. Participation of LF in iron regulation is also mediated via stabilization of iron-sensitive hypoxia-inducible factors-1 alpha and -2 alpha [65,66]. These transcription factors up-regulate the synthesis of erythropoietin, which demonstrated neuroprotective effects distinct from its antianemic functions [67].…”