Suppression of hypoxia-induced HIF-1α and of angiogenesis in endothelial cells by
            <i>myo</i>
            -inositol trispyrophosphate-treated erythrocytes

Kiéda, Claudine; Greferath, Ruth; Silva, Claire Crola Da; Fylaktakidou, Konstantina C.; Lehn, Jean‐Maríe; Nicolau, Claude

doi:10.1073/pnas.0607109103

Cited by 41 publications

(48 citation statements)

References 36 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our hypothesis was that ITPP could counteract hypoxia-induced angiogenesis. In support of this hypothesis, capillary tube formation by endothelial cells is specifically inhibited in vitro in presence of ITPP-loaded red blood cells made thus capable to release higher amounts of O 2 , while ITPP alone has no effect [11]. In addition, ITPP has no effect on endothelial cell proliferation in vitro (see annexe).…”

Section: Discussionmentioning

confidence: 75%

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

et al. 2007

Self Cite

View full text Add to dashboard Cite

We investigate here the anti-angiogenic properties of the synthetic compound myo-inositol trispyrophosphate (ITPP). By increasing oxy-haemoglobin dissociation, ITPP has the potential to counteract the effects of hypoxia, a critical regulator of angiogenesis and cancer progression. ITPP inhibited angiogenesis of the chorioallantoic membrane (CAM), as analyzed with an original program dedicated to automated quantification of angiogenesis in this model. ITPP also markedly reduced tumor progression and angiogenesis in an experimental model of U87 glioma cell nodules grafted onto the CAM. These results point out the potential of ITPP for the development of a new class of anti-angiogenic and anti-cancer compounds.

show abstract

Section: Discussionmentioning

confidence: 75%

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this report, RBCs were treated with myoinositol trispyrophosphate (allosteric modifier of oxygen affinity), which caused a 7 mm Hg drop in the RBC P 50 . Addition of treated RBCs to hypoxia endothelial cells led to a considerable suppression in HIF-1␣ activity (5-fold) as well as vascular endothelial growth factor (1.29-fold) (Kieda et al, 2006).…”

Section: Plasma Reductive Capacity and Hb Oxygen And Redox Kinetics 55mentioning

confidence: 99%

Effects of Endogenous Ascorbate on Oxidation, Oxygenation, and Toxicokinetics of Cell-Free Modified Hemoglobin after Exchange Transfusion in Rat and Guinea Pig

Buehler¹,

D’Agnillo²,

Hoffman³

et al. 2007

J Pharmacol Exp Ther

116

View full text Add to dashboard Cite

Chemically modified hemoglobin (Hb) solutions are promising oxygen therapeutics; however, these agents are prone to intravascular oxidation. Using a 50% exchange transfusion (ET) model with bovine polymerized hemoglobin (PolyHbBv), we examined heme oxidation, oxygenation markers, and toxicokinetics in rats, an ascorbic acid (AA)-producing species, and in guinea pigs, a non-AA-producing species. Plasma AA decreased by 50% in guinea pigs after ET, but it was unchanged in rats for the first 20 h post-ET. Both species cleared PolyHbBv from the circulation at similar rates. However, exposure to ferric PolyHbBv over time was 5-fold greater in the guinea pig. Mass spectrometry analysis of plasma revealed oxidative modifications within the tetrameric fraction of PolyHbBv in guinea pig. Oxygen equilibrium curves of PolyHbBv measured in plasma after ET were more left-shifted in guinea pigs compared with rats, consistent with increased ferric PolyHbBv formation. Renal hypoxia-inducible factor (HIF)-1␣, whose activity strictly depends on the partial pressure of oxygen increased over time, and it correlated inversely with circulating ferrous PolyHbBv in both species. Interestingly, HIF-1␣ activity was greater in guinea pigs compared with rats at 72 h post-ET. Mean arterial pressure increases were also greater in guinea pigs; however, minimal differences in cardiac and renal pathology were observed in either species. The present findings suggest the importance of plasma AA in maintaining the stability of acellular Hb susceptible to oxidation, and they may be relevant to humans, which display a similar plasma/tissue antioxidant status to guinea pig.Hemoglobin (Hb)-based oxygen carriers (HBOCs) represent a class of complex biological entities being developed as oxygen-bridging agents with volume-expanding properties. Despite their therapeutic promise, HBOCs demonstrate a significant potential for toxicity based on administration of large quantities of Hb into the plasma compartment. Normally Hb remains protected in the red blood cell, where processes exist to reduce oxidized Hb and to modulate nitric oxide (NO) binding. It has become increasingly evident that Hb oxidative toxicity can limit the safety and efficacy of current generation HBOCs (Alayash, 2004). This prompted the design of new strategies aimed at reducing or controlling Hb-oxidative side reactions. In vivo oxidation of cell-free Hb is driven spontaneously and/or chemically by variety of oxidants, including hydrogen peroxide (H 2 O 2 ) and NO. NOinduced oxidation of heme iron has the added complication of producing an immediate elevation in blood pressure as a result of removal of NO (a vasodilator) by Hb. Thus, two primary safety concerns with HBOCs in the extracellular space include hypertension and oxidative stress (Riess, 2001;Alayash, 2004). The latter effect depends on plasma and tissue reductive capacity to maintain the HBOC in a reduced and functional state.HBOCs have generally demonstrated promising safety and efficacy in animals, and, in many cases...

show abstract

“…Previous efforts to modify RBC Hb affinity pharmacologically have been limited by the failure of effector molecules to cross RBC membranes (11,14), short duration of effects (19), and poor solubility in water (20). Because ITPP is both membrane permeant and readily soluble in water (15,16), we considered the possibility that ITPP would be absorbed after oral ingestion.…”

Section: Itpp Increases Exercise Capacity In Normalmentioning

confidence: 99%

“…Because at neutral pH, IP 6 is a partially dissociated polyanion bearing 8 negative charges (13), it is unable to cross the RBC membrane and ex vivo physical methods are required to load erythrocytes (11,14). However, we recently showed that myo-inositol trispyrophosphate (ITPP) hexasodium salt is capable of crossing the RBC plasma membrane and acting as an allosteric effector of Hb, shifting the oxyhemoglobin dissociation curve to higher oxygen pressures (pO 2 ) (15,16), and leading to a marked inhibition of blood vessel formation processes in vitro (16). Accordingly, we tested the hypothesis that systemic administration of ITPP would increase exercise capacity in normal mice and in mice with severe exercise limitation caused by reduced cardiac output as a result of myocardial failure.…”

mentioning

confidence: 99%

Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo -inositol trispyrophosphate

Biolo

Greferath

Siwik

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 ؎ 13% (P ‫؍‬ 0.002). In transgenic mice with severe heart failure caused by cardiacspecific overexpression of G␣q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 ؎ 7% (P ‫؍‬ 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (؉34 ؎ 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1␣ mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.hypoxia ͉ oxygen delivery

show abstract

Suppression of hypoxia-induced HIF-1α and of angiogenesis in endothelial cells by myo -inositol trispyrophosphate-treated erythrocytes

Cited by 41 publications

References 36 publications

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

Effects of Endogenous Ascorbate on Oxidation, Oxygenation, and Toxicokinetics of Cell-Free Modified Hemoglobin after Exchange Transfusion in Rat and Guinea Pig

Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo -inositol trispyrophosphate

Contact Info

Product

Resources

About