ArticleLiterature Review

Iron overload, oxidative stress and vascular dysfunction: Evidences from clinical studies and animal models

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Abstract

Although iron is a metal involved in many in vital processes due to its redox capacity, body iron overloads lead to tissue damage, including the cardiovascular system. While cardiomyopathy was the focus since the 1960s, the impact on the vasculature was comparatively neglected for about 40 years, when clinical studies correlating iron overload, oxidative stress, endothelial dysfunction, arterial stiffness and atherosclerosis reinforced an “iron hypothesis”. Due to controversial results from some epidemiological studies investigating atherosclerotic events and iron levels, well-controlled trials and animal studies provided essential data about the influence of iron, per se, on the vasculature. As a result, the pathophysiology of vascular dysfunction in iron overload have been revisited. This review summarizes the knowledge obtained from epidemiological studies, animal models and “in vitro” cellular systems in recent decades, highlighting a more harmful than innocent role of iron excess for the vascular homeostasis, which supports our proposal to hereafter denominate “iron overload vasculopathy”. Additionally, evidence-based therapeutic targets are pointed out to be tested in pre-clinical research that may be useful in cardiovascular protection for patients with iron overload syndromes.

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... High-iron diets or iron compound injections can cause excessive iron buildup in a variety of tissues, simulating iron overload illnesses in humans. These animal models allow for study of the pathophysiology of iron overload and assessments of the effectiveness of iron chelation therapy [49]. Knockout mice, missing the genes involved in iron management and homeostasis, have helped researchers to understand the molecular pathways driving iron overload and create targeted therapeutics [50]. ...
... Concerning the rodent models discussed above, mutant mice models have been generated to replicate iron overload diseases. Mice with specific mutations in iron metabolism genes, such as Hfe, hepcidin, or transferrin receptors, can be used to explore the molecular processes behind iron excess and chelation [49]. Additionally, high-iron dietary regimens have helped scientists to monitor iron consumption and investigate their effects on long-term iron excess. ...
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Background/Objectives: In the absence of physiological mechanisms to excrete excessive iron, the administration of iron chelation therapy is necessary. Age and hormones have an impact on the absorption, distribution, metabolism, and excretion of the medications used to treat iron excess, resulting in notable sex- and gender-related variances. Methods: Here, we aimed to review the literature on sex and gender in iron overload assessment and treatment. Results: The development of iron chelators has shown to be a successful therapy for lowering the body’s iron levels and averting the tissue damage and organ failure that follows. Numerous studies have described how individual factors can impact chelation treatment, potentially impact therapeutic response, and/or result in inadequate chelation or elevated toxicity; however, most of these data have not considered male and female patients as different groups, and particularly, the effect of hormonal variations in women have never been considered. Conclusions: An effective iron chelation treatment should take into account sex and gender differences.
... Iron is another important micronutrient during gestation that could potentially impact offspring vascular health. It is postulated that iron overload in adults may promote oxidative stress and lead to vascular endothelial dysfunction; a detailed review on this has recently been published by others [37]. All pregnant individuals are recommended to take an iron supplement during pregnancy because of the risk of iron deficiency due to the blood volume expansion that occurs in pregnancy [38]. ...
... • Impaired endothelial-dependent funcƟon [35,67] • Postweaning diet maƩers: only in those weaned a onto control diet and not a high fat diet [42] • Impaired endothelial-dependent funcƟon if exposed only during the suckling period [43] • Impaired endothelial-dependent funcƟon [37,67] • Postweaning diet maƩers: only in those weaned onto a control diet and not a high fat diet [42] • Impaired endothelial-dependent funcƟon if exposed only during the suckling period [43] High fat diet feeding (long-term) ...
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Maternal nutrition during pregnancy may have profound effects on the developing fetus and impact risk for cardiovascular disease later in life. Here, we provide a narrative review on the impact of maternal diet during pregnancy on offspring vascular function. We review studies reporting effects of maternal micronutrient (folic acid, iron) intakes, high-fat diets, dietary energy restriction, and low protein intake on offspring endothelial function. We discuss the differences in study design and outcomes and potential underlying mechanisms contributing to the vascular phenotypes observed in the offspring. We further highlight key gaps in the literature and identify targets for future investigations.
... NTBI are a species of iron with a parenchymal target that is unregulatable and possibly harmful (5,6). Since iron overload can cause the dysfunction of many organs, including the liver, heart, joints, skin, and endocrine glands, it results in a serious clinical condition (7). Additionally, iron overload is a marker of ferroptosis that regulates cell death, leading to LPO accumulation at lethal levels (8,9). ...
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The current study aimed to assess the effective dose of quercetin against iron overload in the adult rabbits by studying the dose response curve through using five successive doses of quercetin on serum iron and total iron binding capacity (TIBC) in iron overload rabbits. Thirty-six of adult male rabbits were used in current study and randomly divided in to the six groups and handled as follows for 28 and 42 days: Control group: rabbits were intraperitoneally (IP) injected with normal saline every 72 hours + normal saline orally each day while rabbits in the T1, T2, T3, T4 and T5 groups were administrated orally quercetin at doses 100,200,300,400 and 500 mg/kg B.W daily respectively and all animal were IP injected with iron dextran at dose of 100 mg/kg every 72 hours. Blood samples were collected after 28 and 42 days from ear vein. The results showed a significant increasing in serum iron of T1 and T2 groups, while T3, T4, and T5 groups not showed any significant difference when compared with control group, while TIBC in T4 and T5 not showed any significant difference when compared with control group after 28 and 42 days of quercetin treatment. Conclusion: As a results, obtained after 28 days of the experiment was used to calculate the ED of quercetin on iron overload which is 350 mg/kg.
... Iron's ability to change valence states enables it to efficiently transport O 2 and facilitate electron transfer, which can lead to the generation of ROS (34). Iron overload increases oxidative stress through Fenton reactions and the upregulation of oxidases (23), ultimately promoting the progression of AS (35). In 1981, Jerome Sullivan introduced the "iron hypothesis, " suggesting that excess iron might contribute to cardiovascular damage and that reducing iron levels could potentially protect against CVDs (36). ...
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Background There is controversy regarding the relationship between serum iron levels and atherosclerotic cardiovascular disease (ASCVD). Objective To investigate the relationship between serum iron levels and ASCVD among older adults using data from the 2009–2018 National Health and Nutrition Examination Survey (NHANES). Methods We performed a cross-sectional analysis involving 8,682 participants aged 60 years and older, with complete data on serum iron levels and confirmed ASCVD status, sourced from the 2009–2018 National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression models were used to examine the association between serum iron levels and ASCVD. To assess the consistency of this association across different demographic groups, subgroup analyses, and interaction tests were performed. Results The group with the highest serum iron levels (fourth quartile, 100–369 μg/dL) exhibited several distinct characteristics: they were the youngest on average (69.57 ± 6.91 years), had the highest proportion of males (61.42%), and the highest hemoglobin levels (14.43 ± 1.33 g/dL). This group also showed the lowest iron supplement usage (19.71 ± 12.85 mg/30 days), white blood cell counts (6.73 ± 2.41 1,000 cells/μL), and serum creatinine levels (0.98 ± 0.45 mg/dL). Moreover, they had higher levels of education and income, a higher likelihood of being married, and a lower body mass index (BMI). Additionally, they had significantly lower rates of diabetes, hypertension, stroke, and heart attacks (all p < 0.05). After adjusting for potential confounders, a linear relationship between serum iron levels and ASCVD was initially observed (OR = 0.97; 95% CI, 0.95–0.99, p < 0.05). However, further analysis using a two-part logistic regression model with an inflection point at 131 μg/dL revealed more nuanced results. For serum iron levels below 131 μg/dL, each 10 μg/dL increase was associated with a 4% decrease in the odds of ASCVD (OR = 0.96; 95% CI, 0.93–0.98, p < 0.001). Conversely, for serum iron levels above 131 μg/dL, each 10 μg/dL increase corresponded to a 1% increase in the odds of ASCVD, though this finding was not statistically significant (OR = 1.01; 95% CI, 0.98–1.08, p > 0.05). Conclusion In the US elderly population, serum iron levels are negatively associated with ASCVD, particularly when serum iron levels are below 131 μg/dL.
... The main cause of damage to kidney tissue is oxidative stress, which increases the formation of free radicals, and these lead to cell sloughing in the collecting tubules that function. It inhibits the function of the nephrons, as a result of the interaction between antioxidants and free radicals, which results in necrosis of the renal tubules and also leads to the formation of holes in the lining of the blood vessels, which causes the exit of red blood cells and leads to bleeding (Dos Santos et al., 2022). ...
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Hyperlipidemia is a common disease that causes serious diseases and damages the kidneys due to increased oxidative stress. The Moringa plant was chosen because it contains antioxidants, including flavonoids, to reduce the level of lipids. The experiment was conducted at the Animal House/Veterinary College/Tikrit University, for a period from 10/1/2023 to 11/7/2024. Experimental rats: 40. Form 8 groups of 5 rats each. The healthy groups were fed a standard diet throughout the experiment, while the infected groups were fed a high-fat diet with 2% cholesterol throughout the experiment. The groups were divided as follows: 1 healthy control, 2 infected control fed a high-fat diet, 3 infected control and dosed with Moringa extract, 4 infected and dosed with atorvastatin, 5 infected control and dosed with the extract + the drug, 6 healthy control fed a standard diet and dosed with the extract. 7 were healthy and were dosed with the drug only, 8 were healthy and were dosed with the extract + the drug. The study was designed to determine the role of Moringa extract compared to the drug atorvastatin in improving risk factors for kidney disease resulting from hyperlipidemia. Biochemical results showed an increase in the levels of urea, creatinine, and uric acid in the hyperlipidemia group, and in the groups that were dosed with the extract and the drug, there was a significant decrease (P≥0.05). As for histological results, they showed histological disorders in the kidneys. The extract and drug were more effective in normalizing tissue lesions. 1 ‫جاسن‬ ‫غنى‬ ‫دمحم،‬ 2 ‫احوذ‬ ‫عاصً‬ ‫قٍس‬ 1،2 ‫العراق‬ ‫كركوك،‬ ‫جاهعة‬ ‫الصرفة،‬ ‫للعلوم‬ ‫التربٍة‬ ‫كلٍة‬ ‫الحٍاة،‬ ‫علوم‬ ‫قسن‬ ‫الخالصة‬ ‫المورٌنجا‬ ‫نبات‬ ‫اختٌار‬ ‫تم‬ ‫التأكسدي،‬ ‫االجهاد‬ ‫زٌادة‬ ‫بسبب‬ ‫بالكلى‬ ‫الضرر‬ ‫وٌلحق‬ ‫خطٌرة‬ ‫امراض‬ ‫ٌسبب‬ ‫شائع،‬ ‫مرض‬ ‫الدهون‬ ‫فرط‬ ‫الدهون‬ ‫مستوى‬ ‫من‬ ‫لتخفض‬ ‫الفالفونوٌدات‬ ‫منها‬ ‫اكسدة‬ ‫مضادات‬ ‫احتوائه‬ ‫بسبب‬ ‫جامعة‬ ‫البٌطرة/‬ ‫كلٌة‬ ‫الحٌوانً/‬ ‫البٌت‬ ‫فً‬ ‫التجربة‬ ‫تمت‬. ‫من‬ ‫لمدة‬ ‫تكرٌت،‬ 1 / 10 / 2023 ‫ا‬ ‫لى‬ 7 / 11 / 2024 ‫التجربة‬ ‫جرذان‬. 40 ‫كونت‬ 8 ‫مجموعة‬ ‫كل‬ ‫مجامٌع‬ 5 ‫السلمٌة‬ ‫المجامٌع‬ ‫جرذان.‬ ‫الدهون‬ ‫عالٌة‬ ‫علٌقة‬ ‫على‬ ‫غذٌت‬ ‫المصابة‬ ‫المجامٌع‬ ‫التجربة،‬ ‫فترة‬ ‫طول‬ ‫قٌاسٌة‬ ‫علٌقة‬ ‫على‬ ‫غذٌت‬ 2 ‫التجربة.‬ ‫فترة‬ ‫طول‬ ‫كولٌسترول‬ % ‫كتالً:‬ ‫المجامٌع‬ ‫تقسمت‬ 1 ‫سلٌمة،‬ ‫سٌطرة‬ 2 ‫على‬ ‫غذٌت‬ ‫مصابة‬ ‫سٌطرة‬ ‫الدهون،‬ ‫عالً‬ ‫غذاء‬ 3 ‫المورٌنجا،‬ ‫بمستخلص‬ ‫جرعت‬ ‫مصابة‬ 4 ‫االتورفاستاتٌن،‬ ‫بعقار‬ ‫وجرعت‬ ‫مصابة‬ 5 ‫العقار،‬ + ‫بالمستخلص‬ ‫جرعت‬ ‫مصابة‬ 6 ‫وجرعت‬ ‫قٌاسٌة‬ ‫علٌقة‬ ‫على‬ ‫غذٌت‬ ‫سلٌمة‬ ‫بالمستخلص،‬ 7 ‫فقط،‬ ‫بالعقار‬ ‫وجرعت‬ ‫سلٌمة‬ 8 ‫مستخل‬ ‫دور‬ ‫لمعرفة‬ ‫الدراسة‬ ‫صممت‬ ‫العقار.‬ + ‫بالمستخلص‬ ‫جرعت‬ ‫سلٌمة‬ ‫ص‬ ً ‫ارتفاعا‬ ‫الكٌموحٌوٌة‬ ‫النتائج‬ ‫أظهرت‬ ‫الدهون.‬ ‫فرط‬ ‫عن‬ ‫الناتجة‬ ‫للكلى‬ ‫الخطر‬ ‫عوامل‬ ‫تحسٌن‬ ‫فً‬ ‫االتورفاستاتٌن‬ ‫بعقار‬ ‫مقارنة‬ ‫المورٌنجا‬ ‫والدواء‬ ‫بالمستخلص‬ ‫جرعتها‬ ‫تم‬ ‫التً‬ ‫المجموعات‬ ‫وفً‬ ‫الدم،‬ ‫شحمٌات‬ ‫فرط‬ ‫مجموعة‬ ‫فً‬ ‫البولٌك‬ ‫حمض‬ ‫الكرٌاتٌنٌن،‬ ‫الٌورٌا،‬ ‫نسبة‬ ‫فً‬ ‫معنو‬ ‫انخفاض‬ ‫حدث‬ (‫ي‬ 0.05 ≥ P ‫والدواء‬ ‫المستخلص‬ ‫وكان‬ ‫الكلى.‬ ‫فً‬ ‫نسٌجٌة‬ ‫اضطرابات‬ ‫أظهرت‬ ‫فقد‬ ‫النسٌجٌة‬ ‫للنتائج‬ ‫بالنسبة‬ ‫أما‬ .) ‫األنسجة.‬ ‫اآلفات‬ ‫تطبٌع‬ ‫فً‬ ‫فعالٌة‬ ‫أكثر
... [34] Figure 7: The role of cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6) in atherosclerosis. [23] IL: Interleukin, TNF: Tumor necrosis factor [29] Figure 9: The role of adhesion molecules (VCAM-1 and ICAM-1) in atherosclerosis [33] drugs. Lipid-lowering therapies, such as statins and PCSK9 inhibitors, possess anti-inflammatory properties [ Figure 11]. ...
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In this review, we examine the evolving importance of inflammation in atherosclerosis, the root cause of heart attacks, and strokes. We analyze the complex processes by which inflammation drives all phases of atherosclerosis and closely assess possible targets for therapy within the inflammatory pathway. For researchers and health-care professionals seeking insight into the crucial role of inflammation in atherosclerosis and its potential for novel therapeutic approaches, this review offers a valuable resource.
... accumulation can lead to tissue damage and oxidative stress in animals (Clauss & Paglia, 2012;Dos Santos et al., 2022), and further studies exploring this increase in blood Fe in animals from UA and TR are important. ...
Article
Studies on the bioaccumulation and toxicity of contaminants in Crocodylians are scarce. We evaluated alterations in concentrations of the nondestructive biomarkers butyrylcholinesterase (BChE), glutathione‐S‐transferase (GST), superoxide dismutase (SOD), and reduced glutathione (GSH), together with bioaccumulation of the metals iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), chronium (Cr), aluminium (Al), and lead (Pb) in Caiman latirostris captured in Tapacurá Reservoir (TR; São Lourenço da Mata, Pernambuco, Brasil), in urbanized areas of Pernambuco State (UA; Brasil) and from the AME Brasil caiman farm (AF; Marechal Deodoro, Alagoas, Brasil); the latter was used as a potential reference with low levels of contamination. For metal analysis, 500 µL of blood was digested in 65% HNO 3 and 30% H 2 O 2 . The samples were analyzed by inductively coupled plasma–optical emission spectrometry. For analysis of biomarkers, an aliquot of blood was centrifuged to obtain plasma in which biochemical assays were performed. Blood concentrations of metals analyzed in animals from AF were lower compared with TR and UA, confirming that animals from the caiman farm could be used as references with low levels of contamination. Iron, Cu, Mn, Al, and Pb exceeded toxic levels for other vertebrates in animals from TR and UA. Butyrylcholinesterase activity showed significant reduction in adults from UA and TR compared with AF. An increase in the activity of GST and GSH, in adults of TR and UA in relation to AF, was verified. Superoxide dismutase activity showed a significant reduction in adults of TR in relation to AF, and the concentrations of Cu and Mn were negatively correlated with SOD activity. Animals from UA and TR showed greater concentrations of the analyzed metals compared with reference animals, and changes in biomarkers were seen, confirming the potential of these nondestructive chemical and biological parameters in blood of C. latirostris for biomonitoring of pollution. Environ Toxicol Chem 2024;00:1–18. © 2024 SETAC
... The underlying mechanism is based on iron accumulation causing the activation of multiple signaling pathways and impact cell interactions within the atherosclerotic lesion (Fig. 4). Catalytically active iron is involved in producing reactive oxygen species (ROS) and promoting lipid peroxidation, which is crucial in the development of atherosclerosis [63]. Iron overload is often observed in macrophages and endothelial cells in atherosclerotic lesions. ...
Article
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Iron metabolism plays a crucial role in various physiological functions of the human body, as it is essential for the growth and development of almost all organisms. Dysregulated iron metabolism—manifested either as iron deficiency or overload—is a significant risk factor for the development of cardiovascular disease (CVD). Moreover, emerging evidence suggests that ferroptosis, a form of iron-dependent programed cell death, may also contribute to CVD development. Understanding the regulatory mechanisms of iron metabolism and ferroptosis in CVD is important for improving disease management. By integrating different perspectives and expertise in the field of CVD-related iron metabolism, this overview provides insights into iron metabolism and CVD, along with approaches for diagnosing, treating, and preventing CVD associated with iron dysregulation.
... Since then, extensive research has been performed, accompanied by an ongoing debate regarding this topic, with some studies supporting the iron hypothesis while others did not find a role for iron in cardiovascular risk 5 . In general, laboratory and in vitro studies support the iron hypothesis and in vivo studies report contradictory results [6][7][8] . ...
Article
Full-text available
Iron is hypothesized to be one of the contributors to cardiovascular disease and its levels in the circulation may correlate with cardiovascular risk. The aim of this study is to investigate the mechanisms that underlie the effects of iron on the barrier function of primary human endothelium. We used Human Umbilical Vein Endothelial Cells (HUVEC) to investigate the effects of Fe³⁺ using electric cell-substrate impedance sensing, microscopy, western blot and immunofluorescence microscopy. Exposure to Fe³⁺ caused EC elongation and upregulation of stress-induced proteins. Analysis of barrier function showed a dose-dependent drop in endothelial integrity, which was accompanied by Reactive Oxygen Species (ROS) production and could partly be prevented by ROS scavengers. Inhibition of contractility by the ROCK inhibitor Y27632, showed even more effective rescue of barrier integrity. Using western blot, we detected an increase in expression of the small GTPase RhoB, an inducer of EC contraction, and a small decrease in VE-cadherin, suggestive for an iron-induced stress response. Co-stimulation by TNFα and iron, used to investigate the role of low-grade inflammation, revealed an additive, negative effect on barrier integrity, concomitant with an upregulation of pro-inflammatory markers ICAM-1 and RhoB. Iron induces a response in HUVEC that leads to endothelial activation and a pro-inflammatory state measured by loss of barrier integrity which can be reversed by ROS scavengers, combined with inhibition of contractility. These data suggest that ROS-mediated damage of the vascular endothelium could contribute to the increased cardiovascular risk which is associated with elevated levels of circulating iron.
... (Hsu et al., 2022). Iron overload is a serious clinical disease since it can lead to the dysfunction of several organs, such as the liver, heart, joints, skin, and endocrine glands (Camiolo, 2019;Dos Santos et al., 2022). Excess free iron in the plasma can be produce lipid peroxidation (LPO), which leads to cellular dysfunctions, and several chronic diseases, such as hematological diseases and cancer. ...
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The current study aimed to assess the ability of oral quercetin to treat iron overload and compare it with deferoxamine (DFO). Four groups (each of seven) of adult male New Zealand rabbits with six months of age used in the current study were treated as follows for 28 days: Group C: Animals were injected intraperitoneally (I/P) with normal saline every 72 hours + normal saline orally each day (negative control). T1, T2, and T3 groups were I/P injected with iron dextran (100 mg/kg) once every 72 hours. Additionally, T2 group animals were treated with quercetin (350 mg/kg) once per day for 28 days, and T3 group animals were injected with DFO (125 mg/kg) intramuscularly once per day for 28 days. After 24 hours since the last administration, animals were anesthetized and sacrificed, and blood samples were taken directly from the heart to obtain blood serum. The result showed a significant decrease in serum iron, total iron binding capacity (TIBC), and transferrin saturation percentage in the T2 and T3 groups compared with the T1 group, while, hemoglobin didn't show any significant difference between the T1, T2, and T3 groups. T2 and T3 also showed a significant decrease in malonaldehyde (MDA) and a significant increase in glutathione peroxidase (GPX) concentrations compared with the T1 group. Conclusion: Quercetin has a stronger effect as an iron chelating agent due to its antioxidant properties than deferoxamine in iron-overloaded rabbits. These results suggest that quercetin could be effective in the treatment of iron overload in the clinic.
... On the other hand, iron overload also has adverse consequences for the host, including oxidative stress, vascular dysfunction, ferroptosis, and peroxidation of lipid membranes [45][46][47]. Generally, under pathological conditions, iron overload mainly refers to non-transferrin-bound iron. ...
Article
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Acute lung injury (ALI) has been challenging health care systems since before the COVID-19 pandemic due to its morbidity, mortality, and length of hospital stay. In view of the complex pathogenesis of ALI, effective strategies for its prevention and treatment are still lacking. A growing body of evidence suggests that iron dysregulation is a common characteristic in many subtypes of ALI. On the one hand, iron is needed to produce reactive oxygen species (ROS) as part of the immune response to an infection; on the other hand, iron can accelerate the occurrence of ferroptosis and extend host cell damage. Iron chelation represents a novel therapeutic strategy for alleviating lung injury and improving the survival of patients with ALI. This article reviews the current knowledge of iron homeostasis, the role of iron in ALI development, and potential therapeutic targets.
... Besides, the accumulation of free Fe 2+ in various intracellular iron pools, such as lysosomes and endoplasmic reticulum, promotes oxidative stress through the Fenton reaction that directly generates reactive oxygen species (ROS), or the activation of iron-containing enzymes such as lipoxygenase that catalyze the lipid peroxidation [48]. Angiogenesis is known to be affected by ROS production in a dose-dependent manner, and sustained production or high concentration of ROS due to unbalanced generation and elimination under pathological conditions are detrimental to the vascular system by exacerbating endothelial cell apoptosis [49]. Mechanically, abundant ROS is reported to directly destabilize HIF-1α, resulting in its degradation through ubiquitin-proteasome [50]. ...
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Iron accumulation, which is controlled by transferrin receptor 1 (TfR1), modulates hypoxia-inducible factor-1α (HIF-1α) activation and angiogenesis of hypoxic endothelial cells. The study examined the role of protein interacting with C-kinase 1 (PICK1), a scaffold protein containing PDZ domain, in regulating glycolysis and angiogenesis of hypoxic vascular endothelial cells through its potential effect on TfR1, which features a supersecondary structure that interacts with the PDZ domain. Iron chelator deferoxamine and TfR1 siRNA were employed to assess the impact of iron accumulation on angiogenesis, while the effects of PICK1 siRNA and overexpressing lentivirus on TfR1-mediated iron accumulation were also investigated in hypoxic human umbilical vein vascular endothelial cells (HUVECs). The study found that 72-h hypoxia impaired the proliferation, migration, and tube formation of HUVECs, and reduced the upregulation of vascular endothelial growth factor, HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, and PICK1, while increasing the expression of TfR1 as compared to 24-h hypoxia. Administration of deferoxamine or TfR1 siRNA reversed these effects and led to increased glycolysis, ATP content, and phosphofructokinase activity, along with increased PICK1 expression. PICK1 overexpression improved glycolysis, enhanced angiogenic capacity, and attenuated TfR1 protein upregulation in hypoxic HUVECs, with higher expression of angiogenic markers, which could be significantly reversed by the PDZ domain inhibitor. PICK1 knockdown exerted opposite effects. The study concluded that PICK1 modulated intracellular iron homeostasis, thereby promoting glycolysis and angiogenesis of HUVECs in response to prolonged hypoxia, at least in part, by regulating TfR1 expression.
... Oral or IV Fe supplementation increases hemoglobin concentration and thus prevents and treats all forms of anemia (6,(8)(9)(10). However, Fe overload increases the level of oxidative stress in the human body (20) and increases the risk of developing other diseases during pregnancy, such as GDM (12) and preeclampsia (21). Moreover, long-term periconceptional Fe supplementation of more than 30 mg/d was associated with increased GDM risk in a large prospective cohort of pregnant Chinese women (12). ...
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Background and Aims The association between serum concentrations of metal nutrients in pregnancy and postpartum anemia has not been widely studied. This study aimed to determine this association in a large retrospective cohort study. Methods We included 14,829 Chinese women with singleton pregnancies. Serum concentrations of metals before 28 weeks of gestation, the occurrence of postpartum anemia and other potential covariates were obtained from their laboratory or medical records. Cox regression and restricted cubic spline regression models were used to explore the relationship between serum concentrations of metal nutrients in pregnancy and postpartum anemia. Results After adjustment for covariates, higher concentrations of iron (Fe), magnesium (Mg) and zinc (Zn) and lower concentrations of copper (Cu) were associated with a lower risk of postpartum anemia. Compared with those whose serum concentrations of metal nutrients were in the bottom quintile (Q1), the hazard ratios (HRs) of those whose serum concentrations of metal nutrients were in the top quintile (Q5) were 0.57 (95% confidence interval (CI): 0.50, 0.64) for Fe, 0.67 (95% CI: 0.60, 0.76) for Mg, 0.82 (95% CI: 0.73, 0.93) for Zn, and 1.44 (95% CI: 1.28, 1.63) for Cu. L-shaped curve relationships were found between increasing concentrations of Fe, Mg, and Zn and incidence of postpartum anemia. Higher serum concentrations of Cu were associated with an increased risk of postpartum anemia. Serum concentrations of Fe in Q5 were associated with a lower risk of postpartum anemia when they coincided with serum concentrations of Mg in Q5, Zn in Q5, or Cu in Q1. Conclusion Higher serum concentrations of Fe, Mg, and Zn, and lower serum concentrations of Cu were associated with a lower risk of postpartum anemia among pregnant women.
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Background There are conflicting results among studies on the association between serum ferritin (SF) and metabolic syndrome (MetS), and by groups of sex/menopausal status. To date, there are no studies on British populations. The SF‐MetS association might be U/J‐shaped. We evaluated whether SF was independently associated with MetS (harmonized definition) in people from Shetland, Scotland. Methods We analysed cross‐sectional data from the Viking Health Study‐Shetland (589 premenopausal women [PreMW], 625 postmenopausal women [PostW] and 832 men). Logistic regressions using two approaches, one with the lowest sex and menopausal status‐specific ferritin quartile (Q) as the reference and other using the middle two quartiles combined (2–3) as the reference, were conducted to estimate the SF‐MetS association. The shape of the association was verified via cubic spline analyses. The associations were adjusted for age, inflammatory and hepatic injury markers, alcohol intake, smoking and BMI. Results Prevalence of MetS was 18.3%. Among PostMW both low and high SF were associated with MetS (fully adjusted odds ratios [95% confidence interval] compared to the middle two quartiles combined were: 1.99 [1.17–3.38] p =.011 for Q1 and 2.10 [1.27–3.49] p =.004 for Q4) This U ‐shaped pattern was confirmed in the cubic spline analysis in PostMW with a ferritin range of 15–200 ug/L. In men, a positive association between ferritin quartiles with Q1 as the reference, did not remain significant after adjustment for BMI. Conclusion Extreme quartiles of iron status were positively associated with MetS in PostMW, while no SF‐MetS associations were found in men or PreMW. The ferritin‐MetS association pattern differs between populations and U/J‐shaped associations may exist.
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Anaemia is one of the most common complications of chronic kidney disease (CKD), having a significant impact on quality-of-life, and is also associated with a number of adverse clinical outcomes. Its pathogenesis is multifactorial, caused largely by an inadequate production of erythropoietin from the diseased kidneys, with iron deficiency, inflammation, shortened red cell lifespan, and enhanced blood loss also being contributory factors. The management of this condition was transformed in the late-1980′s by the advent of recombinant human erythropoietin (epoetin) manufactured in Chinese hamster ovary cells, and treatment paradigms have developed over the last three decades, largely focusing on a combination of epoetin or its analogues (erythropoiesis-stimulating agents; ESAs) along with iron supplementation, often administered intravenously due to increased hepcidin levels limiting iron absorption from the gut. Indeed, in patients with early CKD and iron deficiency, iron per se may be sufficient to improve the anaemia, delaying the need for ESA therapy. Other causes of anaemia should be excluded and corrected (if possible) before resorting to treatment with ESAs and iron. More recently, the HIF-prolyl hydroxylase inhibitors have entered the therapeutic arena; these are orally-active agents that upregulate endogenous erythropoietin production as well as a number of iron-regulatory genes which may also enhance erythropoiesis. The latter drugs are highly efficacious, and may have advantages in inflammatory conditions causing resistance to conventional ESA therapy, but concerns exist regarding their safety, particularly in the longer term. This article reviews the current standards of treatment, as well as recent novel developments in the management of anaemia in CKD.
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Ferroptosis is a new non-apoptotic form of regulatory cell death, which is characterized by intracellular iron overload and excessive accumulation of lipid peroxides and reactive oxygen species (ROS). Ferroptosis is closely related to intracellular iron, amino acid, and lipid metabolism disorders. Ferroptosis is increasingly recognized as an important process mediating the pathogenesis and progression of acute ischemic stroke, and it can be involved in influencing acute ischemic stroke and acute ischemic stroke risk factors atherosclerosis, atrial fibrillation, hypertension, diabetes mellitus, and obstructive sleep apnea. Therefore, understanding the mechanisms of ferroptosis regulation in different diseases may have significant implications for the preventive treatment and improvement of prognosis in patients with acute ischemic stroke and patients with risk factors for acute ischemic stroke. This article reviews not only the specific important mechanisms of ferroptosis in the development of acute ischemic stroke, but also the relevant associations between risk factors for acute ischemic stroke and ferroptosis, and describes the current limitations and future directions of ferroptosis in the pathogenesis of acute ischemic stroke and its risk factors.
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Despite several decades of study, whether iron is involved in the development of atherosclerosis remains a controversial and unresolved issue. Here, we focus on the up-to-date advances in studies on role of iron in atherosclerosis and discuss possible reasons why patients with hereditary hemochromatosis (HH) do not show any increased incidence of atherosclerosis. In addition, we analyze conflicting results concerning the role of iron in atherogenesis from several epidemiological and animal studies. We argue that atherosclerosis is not observed in HH because iron homeostasis in the arterial wall, the actual location of atherosclerosis, is not significantly affected, and support a causal link between iron in the arterial wall and atherosclerosis.
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Despite the important role of iron in cellular homeostasis, iron overload (IO) is associated with systemic and tissue deposits which damage several organs. In order to reduce the impact caused by IO, invasive diagnosis exams (e.g., biopsies) and minimally invasive methods were developed including computed tomography and magnetic resonance imaging. However, current diagnostic methods are still time-consuming and expensive. A cost-effective solution is using Fourier-transform infrared spectroscopy (FTIR) for real-time and molecular-sensitive biofluid analysis during conventional laboratory exams. In this study, we performed the first evaluation of the accuracy of FTIR for IO diagnosis. The study was performed by collecting FTIR spectra of plasma samples of five rats intravenously injected with iron-dextran and five control rats. We developed a classification model based on principal component analysis and supervised methods including J48, random forest, multilayer perceptron, and radial basis function network. We achieved 100% accuracy for the classification of the IO status and provided a list of possible biomolecules related to the vibrational modes detected. In this preliminary study, we give a first step towards real-time diagnosis for acute IO or intoxication. Furthermore, we have expanded the literature knowledge regarding the pathophysiological changes induced by iron overload.
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Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.
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Physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases. However, because iron is essential element in many physiological processes including hemoglobin and myoglobin synthesis, thereby playing a role on oxygen transport, many athletes use iron supplement to improve physical performance. Regarding this, iron overload is associated with oxidative stress and damage to various systems, including cardiovascular. Thus, we aimed to identify the vascular effects of aerobic exercise in a rat model of iron overload. Male Wistar rats were treated with 100 mg/kg/day iron-dextran, i.p., 5 days a week for 4 weeks, and then underwent aerobic exercise protocol on a treadmill at moderate intensity, 60 min/day, 5 days a week for 8 weeks. Exercise reduced vasoconstrictor response of isolated aortic rings by increasing participation of nitric oxide (NO) and reducing oxidative stress, but these benefits to the vasculature were not observed in rats previously subjected to iron overload. The reduced vasoconstriction in the exercised group was reversed by incubation with superoxide dismutase (SOD) inhibitor, suggesting that increased SOD activity by exercise was lost in iron overload rats. Iron overload groups increased serum levels of iron, transferrin saturation, and iron deposition in the liver, gastrocnemius muscle, and aorta, and the catalase was overexpressed in the aorta probably as a compensatory mechanism to the increased oxidative stress. In conclusion, despite the known beneficial effects of aerobic exercise on vasculature, our results indicate that previous iron overload impeded the anticontractile effect mediated by increased NO bioavailability and endogenous antioxidant response due to exercise protocol.
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Iron overload is harmful to health and associates with intracellular excessive reactive oxygen species (ROS) generation. Nobiletin (Nob) is known to be antioxidant and anti-inflammatory. However, whether Nob can protect endothelial cells against iron overload has not been studied, and the specific mechanism has not yet been elucidated. In this study, we have identified the protective effects of Nob, and its underlying molecular mechanism in human umbilical vein endothelial cells (HUVECs) suffered from iron overload via ROS/ADMA/DDAHII/eNOS/NO pathway. We found that compared with 50 μM iron dextran treatment, co-treatment with 20 μM Nob increased cell viability and decreased lactate dehydrogenase activity. Besides, Nob could upregulate DDAHII expression and activity, promote eNOS phosphorylation to produce more NO, reduce ADMA content, and therefore increase superoxide dismutase, catalase, and glutathione peroxidase activities, and decrease malondialdehyde level and ROS generation. Nob also inhibited mitochondrial permeability transition pore (mPTP) openness and cleaved caspase-3 expression, and decreased apoptosis induced by iron overload. These results were consistent when Nob was replaced by the positive control reagents L-arginine (a competitive substrate of ADMA), cyclosporin A (an mPTP closing agent), or edaravone (a free radical scavenger). The addition of pAD/DDAHII-shRNA adenovirus reversed the above effects of Nob. These data suggested that the protective mechanism of Nob was to inhibit ROS burst, upregulate DDAHII expression and activity, promote eNOS phosphorylation, produce NO, reduce ADMA content, and ultimately alleviate iron overload damage in vascular endothelium.
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Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic level to prevent both deficiency and overload. Iron Regulatory Proteins post-transcriptionally control genes encoding proteins that modulate iron uptake, recycling and storage and are themselves regulated by iron. The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron absorptive enterocytes and iron recycling macrophages. This review emphasizes the most recent results in the field of iron biology, the deregulation of the hepcidin-ferroportin axis in iron disorders and how research results impact on clinical disorders. Insufficient hepcidin production is central to iron overload while hepcidin excess lead to iron restriction. Mutations of hemochromatosis genes result in iron excess by downregulating the liver BMP/SMAD signaling pathway. In iron loading anemias as β-thalassemia an enhanced albeit ineffective erythropoiesis releases erythroferrone that sequesters the BMP receptor ligand BMPs, thereby inhibiting hepcidin. In Iron-Refractory Iron-Deficiency Anemia mutations of the hepcidin inhibitor TMPRSS6 upregulates the BMP/SMAD pathway. Interleukin-6 in acute and chronic inflammation, increases hepcidin levels causing iron-restricted erythropoiesis and anemia of inflammation in the presence of iron replete macrophages. Our improved understanding of iron homeostasis and its regulation is impacting on the established schedules of oral iron treatment and the choice of oral vs intravenous iron in iron deficiency. Moreover it is leading to the development of targeted therapies for iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis.
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It has been recognized that iron overload may harm the body’s health. Vascular endothelial cells (VECs) are one of the main targets of iron overload injury, and the mechanism involved was thought to be related to the excessive generation of reactive oxygen species (ROS). However, the subcellular and temporal characteristics of ROS generation, potential downstream mechanisms, and target organelles in VECs injured by iron overload have not been expounded yet. In this study, we elucidated the abovementioned issues through both in vivo and in vitro experiments. Mice were fed pellet diets that were supplemented with iron for 4 consecutive months. Results showed that the thoracic aortic strips’ endothelium-dependent dilation was significantly impaired and associated with inflammatory changes, noticeable under brown TUNEL-positive staining in microscopy analysis. In addition, the serum content of asymmetric dimethylarginine (ADMA) increased, whereas nitric oxide (NO) levels decreased. Furthermore, the dimethylarginine dimethylaminohydrolase II (DDAHII) expression and activity, as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) in aortic tissue, were inhibited. Human umbilical vein endothelial cells were treated with 50 μ M iron dextran for 48 hours, after which the cell viability, NO content, DDAHII expression and activity, and phosphorylation of eNOS decreased and lactate dehydrogenase and caspase-3 activity, ADMA content, and apoptotic cells significantly increased. After the addition of L-arginine (L-Arg) or pAD/DDAHII, the abovementioned changes were reversed. By dynamically detecting the changes of ROS generation in the cytoplasm and mitochondria and interfering with different aspects of signaling pathways, we have confirmed for the first time that excessive ROS originates from the cytoplasm and activates the ROS-induced ROS release (RIRR) mechanism, leading to mitochondrial dysfunction. Together, our data suggested that excessive free iron ions produced excess ROS in the cytoplasm. Thus, excess ROS create one vicious circle by activating the ADMA/eNOS/DDAHII/NO pathway and another vicious circle by activation of the RIRR mechanism, which, when combined, induce a ROS burst, resulting in mitochondrial dysfunction and damaged VECs.
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Background and Purpose Damage to the vasculature caused by chronic iron‐overload in both humans and animal models, is characterized by endothelial dysfunction and reduced compliance. In vitro, blockade of the angiotensin II AT1 receptors reversed functional vascular changes induced by chronic iron‐overload. In this study, the effect of chronic AT1 receptor blockade on aorta stiffening was assessed in iron‐overloaded rats. Experimental Approach Male Wistar rats were treated for 15 days with saline as control group, iron dextran 200 mg·kg⁻¹·day⁻¹, 5 days a week (iron‐overload group), losartan (20 mg·kg⁻¹·day⁻¹ in drinking water), and iron dextran plus losartan. Mechanical properties of the aorta were assessed in vivo. In vitro, aortic geometry and biochemical composition were assessed with morphometric and histological methods. Key Results Thoracoabdominal aortic pulse wave velocity (PWV) increased significantly, indicating a decrease in aortic compliance. Co‐treatment with losartan prevented changes on PWV, β‐index, and elastic modulus in iron‐overloaded rats. This iron‐related increase in PWV was not related to changes in aortic geometry and wall stress. but to increased elastic modulus/wall stress ratio, suggesting that a change in the composition of the wall was responsible for the stiffness. Losartan treatment also ameliorated the increase in aorta collagen content of the iron‐overload group, without affecting circulating iron or vascular deposits. Conclusions and Implications Losartan prevented the structural and functional indices of aortic stiffness in iron‐overloaded rats, implying that inhibition of the renin–angiotensin system would limit the vascular remodelling in chronic iron‐overload.
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Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis. ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
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Iron, the most abundant transition metal element in the human body, plays an essential role in many physiological processes. However, without a physiologically active excretory pathway, iron is subject to strict homeostatic processes acting upon its absorption, storage, mobilization, and utilization. These intricate controls are perturbed in primary and secondary hemochromatoses, leading to a deposition of excess iron in multiple vital organs including the heart. Iron overload cardiomyopathy is the leading cause of mortality in patients with iron overload conditions. Apart from mechanical deterioration of the siderotic myocardium, arrhythmias reportedly contribute to a substantial portion of cardiac death associated with iron overload. Despite this significant impact, the cellular mechanisms of electrical disturbances in an iron-overloaded heart are still incompletely characterized. This review article focuses on cellular electrophysiological studies that directly investigate the effects of iron overload on the function of cardiac ion channels, including trans-sarcolemmal and sarcoplasmic reticulum Ca2+ fluxes, as well as cardiac action potential morphology. Our ultimate aim is to provide a comprehensive summary of the currently available information that will encourage and facilitate further mechanistic elucidation of iron-induced pathoelectrophysiological changes in the heart.
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Abstract Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.
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Iron overload cardiomyopathy (IOC) is a major cause of death in patients with diseases associated with chronic anemia such as thalassemia or sickle cell disease after chronic blood transfusions. Associated with iron overload conditions, there is excess free iron that enters cardiomyocytes through both L- and T-type calcium channels thereby resulting in increased reactive oxygen species being generated via Haber-Weiss and Fenton reactions. It is thought that an increase in reactive oxygen species contributes to high morbidity and mortality rates. Recent studies have, however, suggested that it is iron overload in mitochondria that contributes to cellular oxidative stress, mitochondrial damage, cardiac arrhythmias, as well as the development of cardiomyopathy. Iron chelators, antioxidants, and/or calcium channel blockers have been demonstrated to prevent and ameliorate cardiac dysfunction in animal models as well as in patients suffering from cardiac iron overload. Hence, either a mono-therapy or combination therapies with any of the aforementioned agents may serve as a novel treatment in iron-overload patients in the near future. In the present article, we review the mechanisms of cytosolic and/or mitochondrial iron load in the heart which may contribute synergistically or independently to the development of iron-associated cardiomyopathy. We also review available as well as potential future novel treatments.
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In CKD patients, arteriosclerotic lesions, including calcification, can occur in vascular smooth muscle cells in a process called Moenckeberg's medial arteriosclerosis. Iron overload induces several complications, including the acceleration of arteriosclerosis. However, the relationship between Moenckeberg's arteriosclerosis in vascular smooth muscle cells and iron accumulation has remained unknown. We tested the accelerated effect of iron on calcification in cultured human aortic vascular smooth muscle cells (HASMCs). After establishment of this model, we performed a microarray analysis using mRNA from early stage culture HASMCs after iron stimulation with or without TNF-alpha stimulation. The role of interleukin-24 (IL-24) was confirmed from candidate genes that might contribute to calcification. HASMCs demonstrated calcification induced by iron and TNF-alpha. Calcification of HASMCs was synergistically enhanced by stimulation with both iron and TNF-alpha. In the early phase of calcification, microarray analysis revealed up-regulation of IL-24. Stimulation of HASMCs by IL-24 instead of iron induced calcification. The anti-IL-24 antibody reversed the effect of IL-24, supporting the important role of IL-24 in HASMCs calcification. In conclusion, iron-induced calcification in vascular smooth muscle cells occurred via IL-24, IL-24 was increased during the calcification process induced by iron, and IL-24 itself caused calcification in the absence of iron.
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Cardiovascular diseases (CVD) are the main cause of mortality and it represents a significant percentage of hospitalizations. In the scenario of minimization of costs of the health system, methods that identify subclinical CVD would be important. Some guidelines include the measures of aortic stiffness and intima-media thickness of the carotid artery as methods to identify subclinical CVD in hypertensive patients. The pulse wave velocity (PWV) is the gold standard for the evaluation of arterial stiffness. In this review, we report the pathophysiology, the determinants of arterial stiffness, and justify its inclusion in the assessment of hypertensive patient due its direct association with cardiovascular risk, as show in the I Diretriz Brasileira de Prevenção Cardiovascular. In addition, we raised the main genetic studies of this phenotype, due to its complexity, can be modulated by dozens of genes. However, a better understanding of the relationship genetic-arterial stiffness and, even an intervention based on genotypes, should be achieved in future studies.
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The mechanisms that promote liver injury in nonalcoholic fatty liver disease (NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis. © The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
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Iron is a microelement with the most completely studied biological functions. Its wide dissemination in nature and involvement in key metabolic pathways determine the great importance of this metal for uniand multicellular organisms. The biological role of iron is characterized by its indispensability in cell respiration and various biochemical processes providing normal functioning of cells and organs of the human body. Iron also plays an important role in the generation of free radicals, which under different conditions can be useful or damaging to biomolecules and cells. In the literature, there are many reviews devoted to iron metabolism and its regulation in proand eukaryotes. Significant progress has been achieved recently in understanding molecular bases of iron metabolism. The purpose of this review is to systematize available data on mechanisms of iron assimilation, distribution, and elimination from the human body, as well as on its biological importance and on the major iron-containing proteins. The review summarizes recent ideas about iron metabolism. Special attention is paid to mechanisms of iron absorption in the small intestine and to interrelationships of cellular and extracellular pools of this metal in the human body.
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Chronic hemolytic anemia has increasingly been identified as an important risk factor for the development of pulmonary hypertension (PH). Within the thalassemia syndromes, there are multiple mechanisms, both distinct and overlapping, by which PH develops and that differ among β-thalassemia major or intermedia patients. PH in β-thalassemia major correlates with the severity of hemolysis, yet in patients whose disease is well treated with chronic transfusion therapy, the development of PH can be related to cardiac dysfunction and the subsequent toxic effects of iron overload rather than hemolysis. β-Thalassemia intermedia, on the other hand, has a higher incidence of PH owing to the low level of hemolysis that exists over years without the requirement for frequent transfusions, while splenectomy is shown to play an important role in both types. Standard therapies such as chronic transfusion have been shown to mitigate PH, and appropriate chelation therapy can avoid the toxic effects of iron overload, yet is not indicated in many patients. Limited evidence exists for the use of pulmonary vasodilators or other therapies, such as l-carnitine, to treat PH associated with thalassemia. Here, we review the most recent findings regarding the pathogenic mechanisms, epidemiology, presentation, diagnosis, and treatment of PH in thalassemia syndromes.
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Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world-wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron-overload cardiomyopathy. Murine iron-overload models showed cardiac iron-overload, increased oxidative stress, altered Ca2+ homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca2+ homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload.
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Recent evidence shows that iron induces the endocytosis of the iron transporter dimetal transporter 1 (DMT1) during intestinal absorption. Iron-induced DMT1 internalization may underlay the mucosal block, a regulatory response that down-regulates intestinal iron uptake after a dose of iron. In this work, we investigated the participation of reactive oxygen species (ROS) in the establishment of this response. Using selective surface protein biotinylation of polarized Caco-2 cells, we determined the kinetics of DMT1 internalization from the apical membrane after an iron challenge. The initial decrease in DMT1 levels in the apical membrane induced by iron was followed by increased levels of DMT1. Addition of Fe(2+), but not of Cd(2+), Zn(2+), Cu(2+) or Cu(1+), induced the production of intracellular ROS, as detected by 2',7'-dichlorofluorescein. Pre-incubation with the antioxidant N-acetyl-L-cysteine (NAC) resulted in increased DMT1 at the apical membrane prior to and after addition of iron. Similarly, pre-incubation with the hydroxyl radical scavenger dimethyl sulfoxide (DMSO) resulted in the enhanced presence of DMT1 at the apical membrane. The decrease of DMT1 levels at the apical membrane induced by iron was associated with decreased iron uptake rates. A kinetic mathematical model based on operational rate constants of DMT1 endocytosis and exocytosis is proposed. The model qualitatively captures the experimental observations and accurately describes the effect of iron, NAC, and DMSO on the apical distribution of DMT1. Taken together, our data suggest that iron uptake induces production of ROS, which modify DMT1 endocytic cycling, thus changing the iron transport activity at the apical membrane. Copyright © 2015, American Journal of Physiology - Cell Physiology.
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Iron accumulation within the arterial wall has been hypothesized to promote atherosclerosis progression. Aim of this study was to evaluate whether the hormone hepcidin and iron stores are associated with arterial stiffness in subjects with essential hypertension. Circulating hepcidin, ferritin, and mutations in the hemochromatosis gene were compared between subjects included in the first vs. third tertile (n=284 each) of carotid-femoral pulse wave velocity (PWV) in an unselected cohort of patients with arterial hypertension. At univariate logistic regression analysis, high PWV was associated with higher ferritin levels (p=0.010), but lower hepcidin (p=0.045), and hepcidin ferritin/ratio (p<0.001). Hemochromatosis mutations predisposing to iron overload were associated with high PWV (p=0.025). At multivariate logistic regression analysis, high aortic stiffness was associated with older age, male sex, lower BMI, higher systolic blood pressure and heart rate, hyperferritinemia (OR 2.05, 95% c.i. 1.11-3.17 per log ng/ml; p=0.022), and lower circulating hepcidin concentration (OR 0.29, 95% c.i. 0.16-0.51 per log ng/ml; p<0.001). In subgroup analyses, high PWV was associated with indices of target organ damage, including micro-albuminuria (n=125, p=0.038), lower ejection fraction (n=175, p=0.031), cardiac diastolic dysfunction (p=0.004), and lower S wave peak systolic velocity (p<0.001). Ferritin was associated with cardiac diastolic dysfunction, independently of confounders (p=0.006). In conclusion, hyperferritinemia is associated with high aortic stiffness and cardiac diastolic dysfunction, while low circulating hepcidin with high aortic stiffness.
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New findings: What is the central question of this study? The current literature indicates the oxidative stress as playing a major role in the iron-overload. Although exercise is a well-established approach to treat/prevent cardiovascular diseases, its effects on iron-overload are not known. What is the main finding and its importance? Moderate-intensity aerobic training had benefits on a rodent model of iron-overload cardiomyopathy by improving the heart antioxidant capacity. After further confirmation by translational and clinical studies, we should consider using this non-pharmacological, high accessible and easy executable adjuvant approach allied to other therapies for improving the life quality of iron-overloaded patients. Abstract: Iron is an essential micronutrient in several life processes, but its excess can damage organs due to oxidative stress, with cardiomyopathy being the leading cause of death in iron overloaded patients. Although exercise has long been considered as cardioprotective tool, its effects on the iron overload are not known. This study was designed to investigate the effects of moderate-intensity aerobic training in rats previously submitted to chronic iron overload. Wistar rats received intraperitoneal injections of iron-dextran 100 mg/kg, 5 days/week for 4-weeks and then, rats were kept sedentary or exercised (60 min/day, progressive aerobic training, 60-70% maximal speed, 5 days/week on a treadmill) for the following 8-weeks. Thereafter, haemodynamics was recorded and blood sample, liver and heart were collected. Myocardial mechanics of papillary muscles was assessed in vitro, and cardiac remodelling was evaluated by histology and immunoblotting. Iron overload led to liver iron deposition, fibrosis and increased serum alanine aminotransferase and aspartate aminotransferase. Moreover, cardiac iron accumulation was accompanied by impaired myocardial mechanics, increased cardiac collagen type I and lipid peroxidation (TBARS), and CK-MB release to serum. Although exercise did not influence iron levels, tissue injury markers were significantly reduced. Likewise, myocardial contractility and inotropic responsiveness were improved in exercised rats, in association with increased endogenous antioxidant enzyme catalase. In conclusion, moderate-intensity aerobic exercise was associated with attenuated oxidative stress and cardiac damage in a rodent model of iron overload, thereby suggesting its potential role as a non-pharmacological adjuvant therapy for iron overload cardiomyopathy. This article is protected by copyright. All rights reserved.
Article
Iron is a necessary element for life; however, excess iron leads to oxidative stress by the Fenton reaction. Iron deficiency is prevalent in patients with heart failure, while iron overload is associated in the pathogenesis of atherosclerosis. These findings suggest the “iron paradox” in cardiovascular diseases. Iron metabolism in cardiovascular diseases is complex, and the mechanisms regulating systemic and cellular iron metabolism in cardiovascular diseases remain completely unknown. In this review, we focus on the role of iron in cardiovascular diseases.
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Hereditary Hemochromatosis is a condition caused by defects in iron‐sensing genes leading to parenchymal iron loading. If diagnosed early and treated appropriately, many of the complications, including liver fibrosis, cirrhosis and liver cancer, arthritis, cardiomyopathy and diabetes, were thought to be avoided. As iron reduction by venesection became the mainstay of HH treatment before the introduction of evidence‐based medicine, its efficacy has never been the subject of high‐level clinical research. Here we provide a systematic review of iron reduction in HH, including 24 studies and 6000 patients. While strong deductions are prohibited by an absence of robust clinical trial data, the purported benefits of venesection are reviewed and we report an improvement in fatigue, liver function tests and fibrosis, and overall survival. In conclusion, these findings, coupled with the absence of an alternative, low‐cost, effective and tolerable therapy, suggests venesection will remain the mainstay of treatment in HH for decades to come.
Article
Background Five main genes are associated with hemochromatosis; however, current studies show that, in addition to these genes, others may be associated with primary iron overload (IO). One of these is the bone morphogenetic protein 6 (BMP6), which encodes a protein that modulates hepcidin synthesis and, consequently, iron homeostasis. Aim To identify BMP6 gene pathogenic variants in patients with IO and non-homozygous genotype for the HFE p.Cys282Tyr mutation. Materials and methods Fifty-three patients with primary IO and non-homozygous genotype for the HFE p.Cys282Tyr were selected. Subsequent bidirectional DNA sequencing of BMP6 exons was performed. Results Two novel variants were found. One at homozygous state p.Gln158Ter (c.472C > T) was pathogenic, the other one at heterozygous state p.Val394Met (c.1180G > A) was of uncertain significance (VUS); the third variant at heterozygous state p.Arg257His (c.770G > A) has already been described and associated with IO. No BMP6 pathogenic variants that would explain iron overload phenotypes were detected in 94% of the studied patients. Conclusion Identification of the BMP6 pathogenic variants in Brazilian patients with primary IO might contribute to the genetic understanding of this phenotype.
Article
Iron is essential for the function of all cells through its roles in oxygen delivery, electron transport, and enzymatic activity. Cells with high metabolic rates require more iron and are at greater risk for dysfunction during iron deficiency. Iron requirements during pregnancy increase dramatically as the mother’s blood volume expands and the fetus grows and develops. Thus, pregnancy is a condition of impending or existing iron deficiency, which may be difficult to diagnose because of limitations to commonly utilized biomarkers such as hemoglobin and ferritin concentrations. Iron deficiency is associated with adverse pregnancy outcomes including increased maternal illness, low birth weight, prematurity and intrauterine growth restriction. The rapidly developing fetal brain is at particular risk of ID, which can occur because of maternal ID, hypertension, smoking, or glucose intolerance. Low maternal gestational iron intake is associated with autism, schizophrenia and abnormal brain structure in the offspring. Newborns with iron deficiency have compromised recognition memory, slower speed of processing and poorer bonding that persist in spite of postnatal iron repletion. Preclinical models of fetal iron deficiency confirm that expected iron-dependent processes such as monoamine neurotransmission, neuronal growth and differentiation, myelination and gene expression are all compromised acutely and long-term into adulthood. This review outlines strategies to diagnose and prevent iron deficiency in pregnancy. It describes the neurocognitive and mental health consequences of fetal iron deficiency. It emphasizes that fetal iron is a key nutrient that influences brain development and function across the lifespan.
Article
Iron overload causes vascular endothelium damage. It has been thought to relate excessive reactive oxygen species (ROS) generation. Tetramethylpyrazine (TMP), an active ingredient of Ligusticum chuanxiong Hort, protects various cells by inhibiting oxidative stress and cascade reaction of apoptosis. However, whether TMP can increase DDAHIIactivity and expression against endothelial cell damage induced by iron overload, and the protective mechanism has not been elucidated. In this study, 50 μM iron dextran and 25 μM TMP were used to co-treat HUVECs for 48 h. TMP could increase cell viability and decrease LDH activity, enhance DDAHIIexpression and activity, p-eNOS/eNOS ratio, NO content, and reduce ADMA level. TMP also showed a strong antioxidant activity with inhibited ROS generation and oxidative stress. Moreover, TMP attenuated mitochondrial membrane potential loss, inhibited mitochondrial permeability transition pore openness, and decreased apoptosis induced by iron overload. While mentioned above, the protective effects of TMP were abolished with the addition of pAD/DDAHII-shRNA. The effects of TMP against iron overload were similar to the positive control groups, L-arginine, a competitive substrate of ADMA, or edaravone, free radical scavenger. These results signify that TMP alleviated iron overload damage in vascular endothelium via ROS/ADMA/ DDAHII/eNOS/NO pathway.
Article
The aberrant accumulation of iron causes vascular endothelium damage, which is thought to be associated with excess reactive oxygen species (ROS) generation. Quercetin (Que), as a flavonoid, has a certain ability to scavenge free radicals. Therefore, we aimed to explore the protective mechanism of Que on iron overload induced HUVECs injury focused on ROS/ADMA/DDAHⅡ/eNOS/NO pathway. In this study, HUVECs was treated with 50 μM iron dextran and 20 μM Que for 48 h. We found that Que attenuated the damages induced by iron, as evidenced by decreased ROS generation, increased DDAHⅡexpression and activity, reduced ADMA level, increased NO content and p-eNOS/eNOS ratio, and eventually caused a decrease in apoptosis. After addition of pAD/DDAHⅡ-shRNA, the effects of Que mentioned above were reversed. Meanwhile, iron overload induced mitochondrial oxidative stress, reduced mitochondrial membrane potential and increased mitochondrial permeability transition pores (mPTP) opening, which were also partially alleviated by Que. In addition, L-arginine (L-Arg), a ADMA competition substrate, ciclosporin A (CsA), a mPTP blocking agent, and edaravone (Eda), a free radical scavenger, were used as positive control reagents. The effects of Que were similar to that of L-Arg, CsA and Eda treatment. These results illustrated that Que could attenuate iron overload induced HUVECs mitochondrial dysfunction via ROS/ADMA/DDAHⅡ/eNOS/NO pathway.
Article
Before the advent of effective iron chelation, death from iron-induced cardiomyopathy occurred in the second decade in patients with transfusion-dependent chronic anemias. The advances in our understanding of iron metabolism; the ability to monitor iron loading in the liver, heart, pancreas and pituitary; and the availability of several effective iron chelators have dramatically improved survival and reduced morbidity from transfusion-related iron overload. Nevertheless, significantly increased survival brings about new complications such as malignant transformation resulting from prolonged exposure to iron, which need to be considered when developing long-term therapeutic strategies. This review discusses the current biology of iron homeostasis and its close relation to marrow activity in patients with transfusion-dependent anemias, and how biology informs clinical approach to treatment.
Article
Iron is an essential element for human life. However, it is a pro-oxidant agent capable of reacting with hydrogen peroxide. An iron overload can cause cellular changes, such as damage to the plasma membrane leading to cell death. Effects of iron overload in cellular biochemical processes include modulating membrane enzymes, such as the Na, K-ATPase, impairing the ionic transport and inducing irreversible damage to cellular homeostasis. To avoid such damage, cells have an antioxidant system that acts in an integrated manner to prevent oxidative stress. In addition, the cells contain proteins responsible for iron transport and storage, preventing its reaction with other substances during absorption. Moreover, iron is associated with cellular events coordinated by iron-responsive proteins (IRPs) that regulate several cellular functions, including a process of cell death called ferroptosis. This review will address the biochemical aspects of iron overload at the cellular level and its effects on important cellular structures.
Article
Introduction: This is the 36th Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of 1 January, 2018, 55 of the nation’s poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.72 [6.90, 12.0] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system. Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. Results: In 2018, 2,530,238 closed encounters were logged by NPDS: 2,099,751 human exposures, 57,017 animal exposures, 368,025 information requests, 5,346 human confirmed nonexposures, and 99 animal confirmed nonexposures. United States PCs also made 2,621,242 follow-up calls in 2018. Total encounters showed a 2.96% decline from 2017, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.261%. All information requests decreased by 15.5%, medication identification (Drug ID) requests decreased by 30.2%, and human exposure cases decreased by 0.729%. Human exposures with less serious outcomes have decreased 2.33% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.45% per year since 2000. Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.8%), household cleaning substances (7.28%), cosmetics/personal care products (6.53%), sedatives/hypnotics/antipsychotics (5.53%), and antidepressants (5.22%). For cases with more serious outcomes, sedative/hypnotics/antipsychotics exposures were the class that increased most rapidly, by 1,828 cases/year (9.21%/year) over the past 18 years. Over just the past 10 years (for cases with the most serious outcomes) antidepressant exposures increased most rapidly, by 1,887 cases/year (7.02%/year). The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (12.1%), household cleaning substances (10.7%), analgesics (9.04%), foreign bodies/toys/miscellaneous (6.87%), and topical preparations (4.69%). Drug identification requests comprised 18.2% of all information requests. NPDS documented 3,111 human exposures resulting in death; 2,582 (83.0%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.
Chapter
Iron is the most abundant trace element in the human body. It is well known that iron is an important component of hemoglobin involved in the transport of oxygen. As a component of various enzymes, it participates in the tricarboxylic acid cycle and oxidative phosphorylation. Iron in the nervous system is also involved in the metabolism of catecholamine neurotransmitters and is involved in the formation of myelin. Therefore, iron metabolism needs to be strictly regulated. Previous studies have shown that iron deficiency in the brain during infants and young children causes mental retardation, such as delayed development of language and body balance, and psychomotor disorders. However, if the iron is excessively deposited in the aged brain, it is closely related to the occurrence of various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia. Therefore, it is important to fully study and understand the mechanism of brain iron metabolism and its regulation. On this basis, exploring the relationship between brain iron regulation and the occurrence of nervous system diseases and discovering new therapeutic targets related to iron metabolism have important significance for breaking through the limitation of prevention and treatment of nervous system diseases. This review discusses the complete research history of iron and its significant role in the pathogenesis of the central nervous system (CNS) diseases.
Article
Aims: We previously demonstrated that iron overload induces endothelial dysfunction and oxidative stress, which could increase the risk for atherosclerosis. However, the iron-related harmfulness under a genetic predisposition to atherosclerosis is still unclear. Here, we have tested the hypothesis that chronic iron overload may change vascular reactivity associated with worsening of the atherosclerotic process in apolipoprotein E knockout (apoE(-/-)) mice. Main methods: Serum and aortas of wild-type (WT) and apoE(-/-) mice injected with iron-dextran (IO, 10 mg/mouse/day, ip) or saline 5 times a week for 4 weeks, were used. Key findings: Iron overload increased serum levels of iron and biomarkers of liver injury and oxidative stress, and iron deposition in the aorta in both lines, but only apoE(-/-) IO mice had intensified hypercholesterolemia and atherosclerosis. By scanning electron microscopy, the small endothelial structural damage caused by iron in WT was worsened in the apoE(-/-) group. However, endothelial dysfunction was found only in the apoE(-/-) IO group, identified by impaired relaxation to acetylcholine and hyperreactivity to phenylephrine associated with reduced nitric oxide modulation. Moreover, tiron and indomethacin attenuated reactivity to phenylephrine with greater magnitude in aortas of the apoE(-/-) IO group. Confirming, there were changes in the antioxidant (superoxide dismutase and catalase) activity, increased expression of cyclooxygenase-2 in the aorta and elevated levels of thromboxane A2 and prostacyclin metabolites in the urine of apoE(-/-) IO. Significance: Our results showed that chronic iron overload intensifies the atherosclerotic process and induces endothelial dysfunction in atherosclerotic mice, probably due to the oxidative stress and the imbalance between the relaxing and contractile factors synthesized by the damaged endothelium.
Article
Background: Iron is essential for many types of biological processes. However, excessive iron can be cytotoxic and can lead to many diseases. Since ferroptosis, which is an iron-dependent regulated form of necrosis, was recently discovered, iron and iron-catalysed oxidative stress have attracted much interest because of their sophisticated mechanism of cellular signalling leading to cell death and associated with various diseases. Scope of review: In this review, we first focus on how iron catalyses reactive oxygen species (ROS). Next, we discuss the roles of iron in cell death and senescence and, in particular, the downstream signalling pathways of ROS. Finally, we discuss the potential regulation mechanism of iron as a therapeutic target for various iron-related diseases. Major conclusions: Both labile iron released from organelles upon various stresses and iron incorporated in enzymes produce ROS, including lipid ROS. ROS produced by iron activates various signalling pathways, including mitogen-activated protein kinase (MAPK) signalling pathways such as the apoptosis signal-regulating kinase 1 (ASK1)-p38/JNK pathway. These ROS-activated signalling pathways regulate senescence or cell death and are linked to cancer, ischaemia-reperfusion injury during transplantation and ageing-related neurodegenerative diseases. General significance: Iron overload damages cells and causes harmful effects on the body through oxidative stress. Thus, understanding the spatiotemporal availability of iron and the role of iron in generating ROS will provide clues for the suppression of ROS and cytotoxic redox-active iron. Moreover, elucidating the molecular mechanisms and signalling pathways of iron-dependent cytotoxicity will enable us to find novel therapeutic targets for various diseases.
Article
Iron is a key micronutrient for the human body and participates in biological processes, such as oxygen transport, storage, and utilization. Iron homeostasis plays a crucial role in the function of the heart and both iron deficiency and iron overload are harmful to the heart, which is partly mediated by increased oxidative stress. Iron enters the cardiomyocyte through the classic pathway, by binding to the transferrin 1 receptor (TfR1), but also through other routes: T‐type calcium channel (TTCC), divalent metal transporter 1 (DMT1), L‐type calcium channel (LTCC), Zrt‐, Irt‐like Proteins (ZIP) 8 and 14. Only one protein, ferroportin (FPN), extrudes iron from cardiomyocytes. Intracellular iron is utilized, stored bound to cytoplasmic ferritin or imported by mitochondria. This cardiomyocyte iron homeostasis is controlled by iron regulatory proteins (IRP). When the cellular iron level is low, expression of IRPs increases and they reduce expression of FPN, inhibiting iron efflux, reduce ferritin expression, inhibiting iron storage and augment expression of TfR1, increasing cellular iron availability. Such cellular iron homeostasis explains why the heart is very susceptible to iron overload: while cardiomyocytes possess redundant iron importing mechanisms, they are equipped with only one iron exporting protein, ferroportin. Furthermore, abnormalities of iron homeostasis have been found in heart failure and coronary artery disease, however, no clear picture is emerging yet in this area. If we better understand iron homeostasis in the cardiomyocyte, we may be able to develop better therapies for a variety of heart diseases to which abnormalities of iron homeostasis may contribute.
Article
Aims Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE−/− FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). Methods and results Compared with normo-ferremic ApoE−/− mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE−/− FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE−/− FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. Conclusion Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis.
Article
A major form of toxicity arises from the ability of iron to redox cycle, that is, to accept an electron from a reducing compound and to pass it on to H2O2 (the Fenton reaction). In order to do so, iron must be suitably complexed to avoid formation of Fe2O3. The ligands determine the electrode potential; this information should be known before experiments are carried out. Only one-electron transfer reactions are likely to be significant; thus two-electron potentials should not be used to determine whether an iron(III) complex can be reduced. Ascorbate is the relevant reducing agent in blood serum, which means that iron toxicity in this compartment arises from the ascorbate-driven Fenton reaction. In the cytosol, an iron(II)-glutathione complex is likely to be the low-molecular weight iron complex involved in toxicity. When physiologically relevant concentrations are used the window of redox opportunity ranges from +0.1V to +0.9V. The electrode potential for non-transferrin-bound iron in the form of iron citrate is slightly lower than +0.1V, and the reduction of iron(III) citrate by ascorbate is slow. The clinically utilised chelators desferrioxamine, deferiprone and deferasirox in each case render iron complexes with large negative electrode potentials, thus being effective in preventing iron redox cycling and the associated toxicity resulting from such activity. There is still uncertainty about the product of the Fenton reaction, HO• or FeO2+.
Article
Iron metabolism is a balancing act, and biological systems have evolved exquisite regulatory mechanisms to maintain iron homeostasis. Iron metabolism disorders are widespread health problems on a global scale and range from iron deficiency to iron-overload. Both types of iron disorders are linked to heart failure. Iron play a fundamental role in mitochondrial function and various enzyme functions and iron deficiency has a particular negative impact on mitochondria function. Given the high-energy demand of the heart, iron deficiency has a particularly negative impact on heart function and exacerbates heart failure. Iron-overload can result from excessive gut absorption of iron or frequent use of blood transfusions and is typically seen in patients with congenital anemias, sickle cell anemia and beta-thalassemia major, or in patients with primary hemochromatosis. This review provides an overview of normal iron metabolism, mechanisms underlying development of iron disorders in relation to heart failure, including iron-overload cardiomyopathy, and clinical perspective on the treatment options for iron metabolism disorders.
Article
Although iron excess is toxic to the cardiovascular system and even that pulmonary hypertension has been reported, the role of iron overload per se remains to be clarified. This study aimed to test the effects of chronic iron-overload in rats on the morphophysiology of resistance pulmonary arteries (RPA) and right ventricle (RV) remodeling. Rats were injected with saline or iron-dextran (10, 100 and 200 mg/kg/day i.p.) for 28 days. Our results indicated increased circulating iron with significant lung deposits. Moreover, rats treated with the highest dose exhibited RV dysfunction and hypertrophy; inward remodeling and increased vasoconstriction of the RPA. Vascular hyperreactivity was accompanied by reduced nitric oxide (NO), and was reversed by incubation with Dimethylsulfoxide, Catalase and Tempol. The NADPH oxidase subunit gp91phox was increased due to iron-overload, and incubation with angiotensin II type-1 receptor (AT1) antagonist losartan not only reduced oxidative stress but also restored vascular function. Thus, we concluded that AT1 pathway plays a role in pulmonary vascular dysfunction by increasing oxidative stress and reducing NO bioavailability, thereby contributing to vascular remodeling and pulmonary hypertension of iron-overload. This finding should instigate future studies on the beneficial impacts of in vivo blockade of AT1 receptor under these conditions.
Article
Background: An iron-overloaded state has been reported to be associated with insulin resistance. On the other hand, conditions such as classical hemochromatosis (where iron overload occurs primarily in the liver) have been reported to be associated with increased insulin sensitivity. The reasons for these contradictory findings are unclear. In this context, the effects of increased intracellular iron per se on insulin signaling in hepatocytes are not known. Methods: Mouse primary hepatocytes were loaded with iron in vitro by incubation with ferric ammonium citrate (FAC). Intracellular events related to insulin signaling, as well as changes in gene expression and hepatocyte glucose production (HGP), were studied in the presence and absence of insulin and/or forskolin (a glucagon mimetic). Results: In vitro iron-loading of hepatocytes resulted in phosphorylation-mediated activation of Akt and AMP-activated protein kinase. This was associated with decreased basal and forskolin-stimulated HGP. Iron attenuated forskolin-mediated induction of the key gluconeogenic enzyme, glucose-6-phosphatase. It also attenuated activation of the Akt pathway in response to insulin, which was associated with decreased protein levels of insulin receptor substrates 1 and 2, constituting insulin resistance. Conclusions: Increased intracellular iron has dual effects on insulin sensitivity in hepatocytes. It increased basal activation of the Akt pathway, but decreased activation of this pathway in response to insulin. General significance: These findings may help explain why both insulin resistance and increased sensitivity have been observed in iron-overloaded states. They are of relevance to a variety of disease conditions characterized by hepatic iron overload and increased risk of diabetes.
Article
Purpose of review: Iron overload cardiomyopathy (IOC) is an important predictor of prognosis in a significant number of patients with hereditary hemochromatosis and hematologic diseases. Its prevalence is increasing because of improved treatment strategies, which significantly improve life expectancy. We will review diagnosis, treatment, and recent findings in the field. Recent findings: The development of preclinical translational disease models during the last years have helped our understanding of specific disease pathophysiological pathways that might eventually change the outcomes of these patients. Summary: IOC is an overlooked disease because of the progressive silent disease pattern and the lack of physicians' expertise. It mainly affects patients with hemochromatosis and hematologic diseases and its prevalence is expected to increase with the improvement in life expectancy of hematologic disorders. Early diagnosis of IOC in patients at risk by means of biochemical parameters and cardiac imaging can lead to early treatment and improved prognosis. The mainstay of treatment of IOC is conventional heart failure treatment, combined with phlebotomies or iron chelation in the context of anemia. The development of preclinical models has provided a comprehensive look into specific pathophysiological pathways with potential treatment strategies that must be sustained by future randomized trials.
Article
Dysmetabolic iron overload syndrome (DIOS) corresponds to mild increase in both liver and body iron stores associated with various components of metabolic syndrome in the absence of any identifiable cause of iron excess. It is characterized by hyperferritinemia with normal or moderately increased transferrin saturation, one or several metabolic abnormalities (increased body mass index with android distribution of fat, elevated blood pressure, dyslipidaemia, abnormal glucose metabolism, steatohepatitis), and mild hepatic iron excess at magnetic resonance imaging or liver biopsy. Alteration of iron metabolism in DIOS likely results from a multifactorial and dynamic process triggered by an excessively rich diet, facilitated by environmental and genetic cofactors and implying a cross-talk between the liver and visceral adipose tissue. Phlebotomy therapy cannot be currently considered as a valuable option in DIOS patients. Sustained modification of diet and life-style habits remains the first therapeutic intervention in these patients together with drug control of increased blood pressure, abnormal blood glucose and dyslipidaemia when necessary.
Article
Background: Aging declines essential physiological functions, and the vascular system is strongly affected by artery stiffening. We intended to define the age- and sex-specific reference values for carotid-to-femoral pulse wave velocity (cf-PWV) in a sample free of major risk factors. Methods and results: The ELSA-Brasil study enrolled 15,105 participants aged 35-74years. The healthy sample was achieved by excluding diabetics, those over the optimal and normal blood pressure levels, body mass index ≤18.5 or ≥25kg/m(2), current and former smokers, and those with self-report of previous cardiovascular disease. After exclusions, the sample consisted of 2158 healthy adults (1412 women). Although cf-PWV predictors were similar between sex (age, mean arterial pressure (MAP) and heart rate), cf-PWV was higher in men (8.74±1.15 vs. 8.31±1.13m/s; adjusted for age and MAP, P<0.001) for all age intervals. When divided by MAP categories, cf-PWV was significantly higher in those which MAP ≥85mmHg, regardless of sex, and for all age intervals. Risk factors for arterial stiffening in the entire ELSA-Brasil population (n=15,105) increased by twice the age-related slope of cf-PWV growth, regardless of sex (0.0919±0.182 vs. 0.0504±0.153m/s per year for men, 0.0960±0.173 vs. 0.0606±0.139m/s per year for women). Conclusions: cf-PWV is different between men and women and even in an optimal and normal range of MAP and free of other classical risk factors for arterial stiffness, reference values for cf-PWV should take into account MAP levels. Also, the presence of major risk factors in the general population doubles the age-related rise in cf-PWV.
Article
In patients with uncomplicated essential hypertension, cardiac output remains within normal ranges and intravascular volume is normal or low, assuming the presence of a sufficient Windkessel effect and usual resistance and compliance calculations. However, mean circulatory pressure is elevated in these patients. In addition, vascular resistance is augmented, and most importantly, the viscoelasticity of the cardiovascular system is substantially impaired. Such considerations are essential to understanding the mechanisms behind carotid–femoral arterial stiffness, a major risk factor in individuals with hypertension. Arterial stiffness, measured from pulse wave velocity, is substantially increased in hypertension even independently of blood pressure levels. Structural vascular changes and endothelial dysfunction are consistently associated with vessel impairments in animal models of hypertension. Increased arterial stiffness has a major effect on pulse pressure (the difference between systolic and diastolic blood pressure), wave reflections, kidney function, and above all, cardiovascular risk. This increased cardiovascular risk is particularly deleterious in patients with hypertension and/or type 2 diabetes mellitus, who are at risk of both renal and cardiovascular events. In this Review, we discuss the importance of arterial stiffness in the diagnosis and management of hypertension and the need for new approaches for the treatment of hypertension in patients with or without diabetes and/or renal impairment.
Article
Iron overload leads to excessive free radical formation and induces cardiovascular dysfunction. Thus, our aim was to investigate the structural and endothelial modulation of vascular tone induced by chronic iron overload in mesenteric arteries. Rats were divided into two groups: the control (vehicle) group and the group treated with iron dextran for 28 days (100 mg/kg, 5 days a week). Chronic iron overload altered the following morpho-physiological parameters of third-order mesenteric resistance arteries: decreased lumen and external diameters; increased wall/lumen ratio and wall thickness; decreased distensibility and increased stiffness; and increased pulse wave velocity. Additionally, iron overload increased the vasoconstrictor response in mesenteric arterial rings in vitro but did not affect the relaxation induced by acetylcholine and sodium nitroprusside. It is suggested that iron overload reduces nitric oxide bioavailability by increasing free radicals, because L-NAME did not shift the concentration-response curve to phenylephrine, but L-NAME plus superoxide dismutase shifted the curve to the left. In vitro assays with DAF-2 and DHE indicated reduced NO production and increased superoxide anion (O2⁻) generation in the iron-overloaded group. Furthermore, tiron, catalase, apocynin and losartan induced reduced reactivity only in iron-overloaded rats. Moreover, increased ACE activity was observed in the mesenteric resistance arteries of iron-overloaded rats accompanied by an increase in gp91phox, catalase, ERK1/2 and eNOS protein expression. In conclusion, these findings show that chronic iron overload induces structural and functional changes in resistance arteries, most likely due to a decrease in NO bioavailability resulting from an increase in O2–production by NADPH oxidase.
Article
Recent advances in iron metabolism have stimulated new interest in iron deficiency (ID) and its anemia (IDA), common conditions worldwide. Absolute ID/IDA, i.e. the decrease of total body iron, is easily diagnosed based on decreased levels of serum ferritin and transferrin saturation. Relative lack of iron in specific organs/tissues, and IDA in the context of inflammatory disorders, are diagnosed based on arbitrary cut offs of ferritin and transferrin saturation and/or marker combination (as the soluble transferrin receptor/ferritin index) in an appropriate clinical context. Most ID patients are candidate to traditional treatment with oral iron salts, while high hepcidin levels block their absorption in inflammatory disorders. New iron preparations and new treatment modalities are available: high-dose intravenous iron compounds are becoming popular and indications to their use are increasing, although long-term side effects remain to be evaluated.
Article
Iron intoxication is related to reactive oxygen species (ROS) production and organic damage including the cardiovascular system, and is a leading cause of poisoning deaths in children. In this study we examined whether a range of ferrous iron (Fe(2+)) concentrations can interfere differently on the myocardial mechanics, investigating the ROS-mediated effects. Developed force of isolated rat papillary muscles was depressed with a concentration- and time-dependency by Fe(2+) 100-1000μM. The contractile response to Ca(2+) was reduced, but it was partially reversed by co-incubation with catalase and DMSO, but not TEMPOL. In agreement, in situ detection of OH• was increased by Fe(2+) whereas O2(•-) was unchanged. The myosin-ATPase activity was significantly decreased. Contractions dependent on the sarcolemal Ca(2+) influx were impaired only by Fe(2+) 1000μM, and antioxidants had no effect. In skinned fibers, Fe(2+) reduced the pCa-force relationship, and pCa50 was right-shifted by 0.55. In conclusion, iron overload can acutely impair myocardial contractility by reducing myosin-ATPase activity and myofibrillar Ca(2+) sensitivity. These effects are mediated by local production of OH• and H2O2. Nevertheless, in a such high concentration as 1000μM, Fe(2+) appears to depress force also by reducing Ca(2+) influx, probably due to a competition at Ca(2+) channels.
Article
Hereditary hemochromatosis (HH) is a genetic disorder of iron overload and subsequent organ damage. Five types of HH are known, classified by age of onset, genetic cause, clinical manifestations and mode of inheritance. Except for the rare form of juvenile haemochromatosis, symptoms do not usually appear until after decades of progressive iron loading and may be triggered by environmental and lifestyle factors. Despite the last decades discovery of genetic and phenotype diversity of HH, early studies showed a frequent involvement of the endocrine glands where diabetes and hypogonadism are the most common encountered endocrinopathies. The pathogenesis of diabetes is still relatively unclear, but the main mechanisms include the loss of insulin secretory capacity and insulin resistance secondary to liver damage. The presence of obesity and/or genetic predisposition may represent addictive risk factor for the development of this metabolic disease. Although old cases of primary gonad involvement are described, hypogonadism is mainly secondary to selective deposition of iron on the gonadotropin-producing cells of the pituitary gland, leading to hormonal impaired secretion. Cases of hypopituitarism or selected tropin defects, and abnormalities of adrenal, thyroid and parathyroid glands, even if rare, are reported. The prevalence of individual gland dysfunction varies enormously within studies for several bias due to small numbers of and selected cases analyzed, mixed genotypes and missing data on medical history. Moreover, in the last few years early screening and awareness of the disease among physicians have allowed hemochromatosis to be diagnosed in most cases at early stages when patients have no symptoms. Therefore, the clinical presentation of this disease has changed significantly and the recognized common complications are encountered less frequently. This review summarizes the current knowledge on HH-associated endocrinopathies.
Article
Iron plays a critical role in a mammal's physiological processes. However, iron tissue deposits have been shown to act as endocrine disrupters. Studies that evaluate the effect of acute iron overload on hypothalamic-pituitary-gonadal (HPG) axis health are particularly sparse. This study demonstrates that acute iron overload leads to HPG axis abnormalities, including iron accumulation and impairment in reproductive tract morphology. Female rats were treated with iron-dextran (Fe rats) to assess their HPG morphophysiology. The increasing serum iron levels due to iron-dextran treatment were positively correlated with higher iron accumulation in the HPG axis and uterus of Fe rats than in control rats. An increase in the production of superoxide anions was observed in the pituitary, uterus and ovary of Fe rats. Morphophysiological reproductive tract abnormalities, such as abnormal ovarian follicular development and the reduction of serum estrogen levels, were observed in Fe rats. In addition, a significant negative correlation was obtained between ovary superoxide anion and serum estrogen levels. Together, these data provide in vivo evidence that acute iron overload is toxic for the HPG axis, a finding that may be associated with the subsequent development of the risk of reproductive dysfunction.
Article
With repeated blood transfusions, patients with thalassemia major rapidly become loaded with iron, often surpassing hepatic metal accumulation capacity within ferritin shells and infiltrating heart and endocrine organs. That pathological scenario contrasts with the physiological one, which is characterized by an efficient maintenance of all plasma iron bound to circulating transferrin, due to a tight control of iron ingress into plasma by the hormone, hepcidin. Within cells, most of the acquired iron becomes protein-associated, as once released from endocytosed transferrin, it is used within mitochondria for the synthesis of protein prosthetic groups or it is incorporated into enzyme active centers, or alternatively sequestered within ferritin shells. A few cell types are also expressing the iron extrusion transporter ferroportin that is under the negative control of circulating hepcidin. However, that latter system only backs up the major cell regulated iron uptake/storage machinery that is poised to maintain a basal level of labile cellular iron for metabolic purposes without incurring potentially toxic scenarios. In thalassemia and other transfusion iron loading conditions, once transferrin saturation exceeds about 70%, labile forms of iron enter into the circulation and can gain access to various types of cells via resident transporters or channels. Within cells, they can attain levels that exceed their ability to chemically cope with labile iron, which has a propensity for generating reactive oxygen species (ROS), thereby inducing oxidative damage. This scenario occurs in the heart of hypertransfused thalassemia major patients who do not receive adequate iron chelation therapy. Iron that accumulates in cardiomyocytes forms agglomerates that are detected by T2⁎ MRI. The labile forms of iron infiltrate the mitochondria and damage cells by inducing noxious ROS formation, resulting in heart failure. The very rapid relief of cardiac dysfunction seen after intensive iron chelation therapy in some patients with thalassemia major is thought to be due to the relief of the cardiac mitochondrial dysfunction caused by oxidative stress or to the removal of labile iron interference with calcium fluxes through cardiac calcium channels. In fact, improvement occurs well before there is any significant improvement in the total level of cardiac iron loading. The oral iron chelator, deferiprone, because of its small size and neutral charge, demonstrably enters cells and chelates labile iron, thereby rapidly reducing ROS formation, allowing better mitochondrial activity and improved cardiac function. Deferiprone may also rapidly improve arrhythmias in patients who do not have excessive cardiac iron. It maintains the flux of iron in the direction hemosiderin to ferritin to free iron, and it allows clearance of cardiac iron in the presence of other iron chelators or used alone. To date, the most commonly used chelator combination therapy is deferoxamine plus deferiprone, while other combinations are in the process of assessment. In summary, it is imperative that patients with thalassemia major have iron chelators continuously present in their circulation to prevent exposure of the heart to labile iron, reduce cardiac toxicity and improve cardiac function. Copyright © 2015. Published by Elsevier Inc.