Treatment of hypoxia‐dependent cardiovascular diseases by myo‐inositol trispyrophosphate (ITPP)‐enhancement of oxygen delivery by red blood cells

Abstract

Heart failure is a consequence of progression hypoxia‐dependent tissue damages. Therapeutic approaches to restore and/or protect the healthy cardiac tissue have largely failed and remain a major challenge of regenerative medicine. The myo‐inositol trispyrophosphate (ITPP) is a modifier of haemoglobin which enters the red blood cells and modifies the haemoglobin properties, allowing for easier and better delivery of oxygen by the blood. Here, we show that this treatment approach in an in vivo model of myocardial infarction (MI) results in an efficient protection from heart failure, and we demonstrate the recovery effect on post‐MI left ventricular remodelling in the rat model. Cultured cardiomyocytes used to study the molecular mechanism of action of ITPP in vitro displayed the fast stimulation of HIF‐1 upon hypoxic conditions. HIF‐1 overexpression was prevented by ITPP when incorporated into red blood cells applied in a model of blood‐perfused cardiomyocytes coupling the dynamic shear stress effect to the enhanced O2 supply by modification of haemoglobin ability to release O2 in hypoxia. ITPP treatment appears a breakthrough strategy for the efficient and safe treatment of hypoxia‐ or ischaemia‐induced injury of cardiac tissue.

Endothelial Cells as Tools to Model Tissue Microenvironment in Hypoxia-Dependent Pathologies

“…Additionally, PTEN activation which leads to the inhibition of PI3K (phosphoinositide 3-kinases) and decreasing tumor AKT (protein kinase B)phosphorylation results in tumor growth reduction [ 156 ]. Moreover, ITPP was described as an effective tool in the treatment of hypoxia-dependent cardiovascular diseases (heart failure) by similar molecular mechanisms [ 185 , 186 ].…”

Right ventricular myocardial oxygen tension is reduced in monocrotaline-induced pulmonary hypertension in the rat and restored by myo-inositol trispyrophosphate

“…This is accompanied by a potent anti-cancer effect in various tumor models in the mouse 14 , 16 . Moreover, we have recently shown that chronic ITPP treatment partially prevents post-myocardial infarction heart failure in the rat model 17 . However effects of ITPP on myocardial pO 2 have never been studied.…”

Tumour suppressor PTEN activity is differentially inducible by myo‐inositol phosphates

“…As demonstrated by us, such activation is possible by myo‐inositol trispyrophosphate derivatives in the cancer, 19 but also in cardiac disease 28,44 treatments. It also led us to hypothesize that PTEN activation is a complex process on which its further induced biological consequences are dependent.…”