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.
Highlights
We have previously shown that inositol trispyrophosphate (ITPP) shifts the oxygen dissociation curve downward, increases tissue oxygen delivery, especially to hypoxic tumours.[11]
As ITPP-charged erythrocytes counteract the effects of hypoxia on cardiomyocytes and do not exert any toxicity, we addressed the question of cardiomyocytes remodelling under such treatment
We show for the first time that ITPP, a novel membrane-permeant allosteric effector of haemoglobin that enhances the oxygen release capacity of RBC by lowering the affinity of Hb for oxygen, partially prevents post-myocardial infarction (MI) left ventricular dilation and impairment of contractility in the rat model of post-MI heart failure, most important markers of heart failure progression and prognosis
Summary
Especially with reduced ejection fraction, is a complex syndrome characterized by ongoing progression of the disease without any external triggering factors.[1]. Cardiac structure and function continue to deteriorate.[2] This progression is believed to be powered by multiple vicious circles that eventually result in end-stage pump failure and patient's death.[1]. They include cardiomyocyte apoptosis and necrosis, resulting in net loss of cardiomyocytes, mitochondrial dysfunction, impaired cardiomyocytes Ca2+ handling, fibrosis, neurohormonal activation and ischaemia.[2]. Studies suggest that intracellular ATP concentration may be 25%-30% lower in the failing human hearts[4] and this process can contribute to heart failure progression. This is probably a multifactorial phenomenon, resulting from reduced oxygen delivery, impaired oxygen utilization in the face of increased oxygen demand (due to increased afterload).[5]. Neither erythropoietin analogs that increased haemoglobin concentration[6] nor intravenous iron that provided an essential element for haemoglobin, and other enzymes involved in cardiac energetics[7] provided unequivocal benefits in human clinical trials, though recent data, including our own work,[8] suggest that iron may be of some value here
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