Abstract
BackgroundIron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells.MethodsHF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production.ResultsHearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells.ConclusionsHF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.
Highlights
Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined
The mechanisms linking iron regulation, energy metabolism and mitochondrial function, were further explored in depth in heart-derived cell cultures H9c2 exposed to the neurohormonal activation typically found in HF
The mRNA and protein levels of the main molecules related to cellular iron uptake, release and storage, were analyzed in HF and control mice
Summary
Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. The sustained activation of these pathways lead to an increased plasma Ang II, epinephrine and Nor levels [5, 6] The inhibition of these neurohormonal systems has demonstrated a consistent reduction in morbidity and mortality in patients with systolic HF and is the basis of modern pharmacological treatment [7, 8]. These effective therapies have failed to promote a complete remission of symptoms and restore life expectancy in many patients. Intravenous iron supplementation has been recommended by European Society of Cardiology (ESC) HF guidelines as a potential therapeutic approach, since the correction of ID with intravenous iron alleviates HF symptoms, reduces risk of hospitalization and improves quality of life [14,15,16]
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