Hemochromatosis Protein (HFE) Knockout Mice As a Novel Model of Hemochromatosis: Implications for Study and Management of Iron-Overload Cardiomyopathy

Zhabyeyev, Pavel; Oudit, Gavin Y.

doi:10.1016/j.cjca.2017.04.013

Cited by 6 publications

(10 citation statements)

References 28 publications

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“…Impaired iron metabolism can be found in many liver diseases, particularly those with genetic hemochromatosis, secondary iron overload, and alcohol-related liver diseases (1,39). Hereditary hemochromatosis is associated with loss-of-function mutations mainly in hemochromatosis, hemojuvelin, or hepcidin genes (9,54,64). In this condition, the liver produces a negligible amount of hepcidin, leading to uncontrolled iron uptake and iron overload (24,31,52,53,61).…”

Section: Introductionmentioning

confidence: 99%

TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease

Zhabyeyev

Das

Basu

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic iron overload results in heart and liver diseases and is a common cause of morbidity and mortality in patients with genetic hemochromatosis and secondary iron overload. We investigated the role of tissue inhibitor of metalloproteinase 3 (TIMP3) in iron overload-mediated tissue injury by subjecting male mice lacking Timp3 ( Timp3) and wild-type (WT) mice to 12 wk of chronic iron overload. Whereas WT mice with iron overload developed diastolic dysfunction, iron-overloaded Timp3 mice showed worsened cardiac dysfunction coupled with systolic dysfunction. In the heart, loss of Timp3 was associated with increased myocardial fibrosis, greater Timp1, matrix metalloproteinase ( Mmp) 2, and Mmp9 expression, increased active MMP-2 levels, and gelatinase activity. Iron overload in Timp3 mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin. Loss of Timp3 enhanced the hepatic inflammatory response to iron overload, leading to greater neutrophil and macrophage infiltration and increased hepatic fibrosis. Expression of inflammation-related MMPs (MMP-12 and MMP-13) and inflammatory cytokines (IL-1β and monocyte chemoattractant protein-1) was elevated to a greater extent in iron-overloaded Timp3 livers. Gelatin zymography demonstrated equivalent increases in MMP-2 and MMP-9 levels in WT and Timp3 iron-overloaded livers. Loss of Timp3 enhanced the susceptibility to iron overload-mediated heart and liver injury, suggesting that Timp3 is a key protective molecule against iron-mediated pathology. NEW & NOTEWORTHY In mice, loss of tissue inhibitor of metalloproteinase 3 ( Timp3) was associated with systolic and diastolic dysfunctions, twofold higher hepatic iron accumulation (attributable to constituently lower levels of ferroportin), and increased hepatic inflammation. Loss of Timp3 enhanced the susceptibility to iron overload-mediated injury, suggesting that Timp3 plays a key protective role against iron-mediated pathology.

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Section: Introductionmentioning

confidence: 99%

TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease

Zhabyeyev

Das

Basu

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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“…Ali and his associates reported that there was no significant difference between MCA pulsatility indices measured before and after anemia treatment (p = 0.573). It had mean values of 1.42 and 1.4 in these time intervals respectively [43].…”

Section: Discussionmentioning

confidence: 90%

Comparative Studies of the Effect of Different Types of Iron Tonics on Umbilical and Middle Cerebral Blood Flow in Cases of Moderate Iron Deficiency Anemia in Late Second Trimester of Pregnant Women

Elbehiry

El-Dakhakhni

Dawood

et al. 2021

JAMMR

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Background: Maternal anemia is frequently associated with premature delivery, reduced neonatal weight, infant iron deficiency, neonatal death, and low Apgar scores at 1 min. It is also suspected to reduce the oxygen supply to the growing fetus, leading to the redistribution of fetal blood flow. This study aims to evaluate the effect of the different types of iron medications given to anemic patients on fetal Doppler indices namely umbilical artery and middle cerebral artery in the late second trimester of pregnancy. Materials and Methods: This cohort prospective study. This study conducted at department of obstetrics and gynecology at Tanta university hospital. Participants consisted of 90 pregnant women during their gestational age (20-28 weeks) they were attended or admitted to obstetric unit.divided into 3 groups. Lactoferrin group included 30 cases received 250 mg lactoferrin capsules once daily for 4 weeks. Iron amino acid chelated group included 30 cases received ferrous bis – glycine chelate (FeBC) 15 mg/day for 4 weeks. Ferrous fumarate group included 30 cases received 350 mg dried ferrous fumarate capsules once daily for 4 weeks. Pre-and post-treatment Doppler measurement of umbilical artery and middle cerebral artery parameter compared 4 weeks after the start of treatment for patients whose anemia successfully treated. Results: Post hoc analysis of maternal serum hemoglobin of the studied groups show insignificant different between the groups. Pre- and Post-treatment follow-up of resistance index (RI) of the studied groups, Pre- and Post-treatment follow-up of pulsatility index (PI) of the studied groups, Post hoc analysis of pulsatility index (PI) of the studied groups and Post hoc analysis of resistance index (RI) of the studied groups show insignificant different between groups. Conclusion: Based on our results, it can be concluded that cerebral vasodilatation due to severe maternal anemia is a reversible condition that can be corrected through the prompt treatment of anemia. Additionally, the three therapeutics tested in the current study showed a comparable effect in treating maternal anemia, with subsequent improvement of doppler indices.

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“…ROS production leads to suppressed SERCA2 function and contractive dysfunction. Lipid peroxidation also attacks the mitochondrial membrane, thereby leading to energy depletion, mitochondrial DNA damage and dysfunction ( Das et al, 2015 ; Zhabyeyev and Oudit, 2017 ; Gordan et al, 2018 ). Theoretically, excessive intracellular Fe 2+ may catalyze the cascade of lipid oxidation, which leads to ferroptosis ( Shayeghi et al, 2005 ).…”

Section: Cardiac Iron Overloadmentioning

confidence: 99%

Heme in Cardiovascular Diseases: A Ubiquitous Dangerous Molecule Worthy of Vigilance

Guo

Zhao

Lin

et al. 2022

Front. Cell Dev. Biol.

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Heme, the protoporphyrin IX iron complex is widely present in the human body and it is involved in oxygen storage, electron transfer, and enzymatic reactions. However, free heme can be toxic as it catalyzes the production of reactive oxygen species, oxidizes lipids and proteins, and causes DNA damage, thereby inducing a pro-inflammatory environment. The generation, metabolism, and degradation of heme in the human body are regulated by precise mechanisms to ensure that heme remains non-toxic. However, in several types of cardiovascular diseases, impaired metabolism and exposure to heme may occur in pathological processes, including neovascularization, internal hemorrhage, ischemia, and reperfusion. Based on years of research, in this review, we aimed to summarize the underlying mechanisms by which heme contributes to the development of cardiovascular diseases through oxidative stress, relative pathway gene expression regulation and phenotypic changes in cells. Excess heme plays a detrimental role in atherosclerosis, heart failure, myocardial ischemia-reperfusion injury, degenerative aortic valve stenosis, cardiac iron overload. Recent researches revealed that in some cases heme involved in cardiac damage though ferroptosis. Thus, heme concentrations beyond normal levels are dangerous. Further research on the role of heme in cardiovascular diseases is needed.

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Hemochromatosis Protein (HFE) Knockout Mice As a Novel Model of Hemochromatosis: Implications for Study and Management of Iron-Overload Cardiomyopathy

Abstract: See article by Djemai et al., pages 904e910 of this issue.

Cited by 6 publications

References 28 publications

TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease

TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease

Comparative Studies of the Effect of Different Types of Iron Tonics on Umbilical and Middle Cerebral Blood Flow in Cases of Moderate Iron Deficiency Anemia in Late Second Trimester of Pregnant Women

Heme in Cardiovascular Diseases: A Ubiquitous Dangerous Molecule Worthy of Vigilance

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