Modulation of the Oxygenation State and Intracellular pH of Erythrocytes by Inositol-Trispyrophosphate Investigated by P NMR Study of 2,3-DPG.

The hypoxic microenvironment is crucial for tumour cell growth and invasiveness. Tumour tissue results from adaptation to reduced oxygen availability. Hypoxia first activates pro-angiogenic signals for alleviation. Pathologic, tumour angiogenesis maintains hypoxia, impairing treatment outcomes. Vessel normalisation requires physioxia. Oxygen delivery by red blood cell (RBC) carrying haemoglobin (Hb) is enhanced by myo-inositol trispyrophosphate (ITPP), an effector of oxygen transport by RBCs. Altering glycolytic activity, it lowers intracellular pH and increases oxygen release from Hb. P NMR tracking of 2,3-diphosphoglycerate (2,3-DPG), allosteric effector of Hb and non-penetrating anion in RBCs, reports on erythrocytes internal environment. P resonances of 2,3-DPG are pH-sensitive, their positions indicate the oxygenation state of RBCs and interactions with effectors such as ITPP. Here we show in vitro and in vivo, that modifying Hb activity through band-3 anion transporter, ITPP enhances oxygen release and controls RBC internal pH. Its blood availability validates applicability of ITPP-based strategies.