Expression of Iron Metabolism Proteins in Patients with Chronic Heart Failure

Abstract

In heart failure, iron deficiency is a common comorbid disease that negatively influences exercise tolerance, number of hospitalizations and mortality rate, and this is why iron iv supplementation is recommended. Little is known about the changes in iron-related proteins in the human HF myocardium. The purpose of this study was to assess iron-related proteins in non-failing (NFH) vs. failing (FH) human myocardium. The study group consisted of 58 explanted FHs; control consisted of 31 NFHs unsuitable for transplantation. Myocardial proteins expressions: divalent metal transporter (DMT-1); L-type calcium channel (L-CH); transferrin receptors (TfR-1/TfR-2); ferritins: heavy (FT-H) or light (FT-L) chain, mitochondrial (FT-MT); ferroportin (FPN), regulatory factors and oxidative stress marker: 4-hydroxynonenal (4-HNE). In FH, the expression in almost all proteins responsible for iron transport: DMT-1, TfR-1, L-CH, except TfR-2, and storage: FT-H/-L/-MT were reduced, with no changes in FPN. Moreover, 4-HNE expression (pg/mg; NFH 10.6 ± 8.4 vs. FH 55.7 ± 33.7; p < 0.0001) in FH was increased. HNE-4 significantly correlated with DMT-1 (r = −0.377, p = 0.036), L-CH (r = −0.571, p = 0.001), FT-H (r = −0.379, p = 0.036), also FPN (r = 0.422, p = 0.018). Reducing iron-gathering proteins and elevated oxidative stress in failing hearts is very unfavorable for myocardiocytes. It should be taken into consideration before treatment with drugs or supplements that elevate free oxygen radicals in the heart.

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

“…Serum levels of sTfR are increased in both patients with an absolute or functional iron deficiency, 43 , 67 since the receptor is upregulated in response to a decrease in cytosolic iron, regardless of cause. However, the failing heart often shows decreased expression of TfR1, 68 , 69 perhaps the result of neurohormonal activation, 70 , 71 which may contribute to an intracellular iron deficiency in cardiomyocytes. However, it is possible that this down‐regulation of TfR1 is modified into an upregulation of TfR1 when myocardial iron stores are depleted.…”

Clinical and Molecular Aspects of Iron Metabolism in Failing Myocytes

“…Furthermore, iron content was negatively correlated with myocardial ferritin, which suggests that iron deficiency was associated with disorders with myocardial iron storage. Further studies confirmed that the expression of total myocardial FT and the expression of individual components, FT-HC, FT-LC, and FT-MTC, were significantly reduced in the group of patients with advanced HF [ 102 ]. The results suggest more complicated relationships between iron transport and metabolism proteins in the failing heart than previously thought.…”

“…The results suggest more complicated relationships between iron transport and metabolism proteins in the failing heart than previously thought. In the iron-cell-transportation proteins, the expression of TfR1, the crucial transporter for iron uptake, was found to be reduced on the mRNA [ 42 ] and protein levels [ 102 ]. Moreover, the expression of transferrin-independent iron channels DMT-1 and L-CH were significantly reduced on the protein levels.…”

“…This pathway is, however, disturbed in HF patients because low iron levels did not increase IRBs content in the myocardial cells. Moreover, in advanced HF, another transcriptional factor connected to oxygen metabolism HIF-1 is significantly decreased in the cardiac myocytes on the protein [ 102 ] and mRNA [ 106 ] levels. This led to attenuation of the cardio-protective effect of the HIF system in HF patients.…”

“…Changes in the expression of iron-metabolism proteins in HF are associated with the modification of iron-regulatory factors. There was a significant reduction in ACO-1 (also known as IREB-1) and IREB-2 proteins in HF patients [ 102 ]. Low cytosolic iron levels should acactivate IREBs to increase iron import and decrease iron escape from the cells [ 105 ].…”