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Heme- and Hemoglobin Stress in Human Diseases 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 9201

Special Issue Editor


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Guest Editor
Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Interests: heme- and hemoglobin-mediated vascular damage; vascular and valvular mineralization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aim of this Special Issue is to promote research concerning the involvement of heme and heme proteins in the pathogenesis of various diseases as well as preventive and therapeutic strategies to minimize damage through associated pathways.

Heme is the principal iron complex in the human body with vital physiological functions and strictly regulated metabolism, responsible for oxygen and electron transport among many other roles. This diverse capability is achieved through the numerous combinations that result from associations of heme with various protein chains.

Under pathological conditions, heme can escape from its safe and functional sanctuaries and interact with cellular domains and tissue constituents, allowing pathophysiologic remodeling. Given the hydrophobic nature of heme, it is no surprise that it easily crosses cell membranes and can synergistically enhance cellular oxidant damage. In addition, through binding, it alters the functions of proteins, lipids, and nucleic acids, affecting signaling pathways, cell differentiation, cell–cell interactions, contractility, etc.

Heme moieties of some heme proteins may react with peroxides, leading to the formation of protein radicals and thereby altering their structures, actions, and functions. Hydrogen sulfide, nitrogen monoxide, and carbon monoxide were shown to have impact on such physiology and pathophysiology.

Of all the sites in the body, the vasculature may be at the greatest risk of harm exhibited by heme and heme proteins, including hemoglobin. Substantial evidence is accumulating regarding the existence of heme and hemoglobin stress as well as adaptation against its damaging effects.

Prof. Dr. József Balla
Guest Editor

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Keywords

  • heme
  • iron
  • heme proteins
  • hemoglobin
  • free radicals
  • hemoglobin oxidation
  • hydrogen sulfide
  • nitrogen monoxide
  • carbon monoxide
  • bilirubin
  • biliverdin
  • heme oxygenase
  • biliverdin reductase
  • ferritin
  • iron metabolism
  • Nrf2
  • Bach-1

Published Papers (3 papers)

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Research

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17 pages, 3340 KiB  
Article
Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1
by Sarah E. Machado, Daryll Spangler, Delores A. Stacks, Victor Darley-Usmar, Gloria A. Benavides, Min Xie, József Balla and Abolfazl Zarjou
Int. J. Mol. Sci. 2022, 23(15), 8300; https://doi.org/10.3390/ijms23158300 - 27 Jul 2022
Cited by 17 | Viewed by 2838
Abstract
Given the abundance of heme proteins (cytochromes) in the mitochondrion, it is evident that a meticulously orchestrated iron metabolism is essential for cardiac health. Here, we examined the functional significance of myocardial ferritin heavy chain (FtH) in a model of acute myocardial infarction. [...] Read more.
Given the abundance of heme proteins (cytochromes) in the mitochondrion, it is evident that a meticulously orchestrated iron metabolism is essential for cardiac health. Here, we examined the functional significance of myocardial ferritin heavy chain (FtH) in a model of acute myocardial infarction. We report that FtH deletion did not alter either the mitochondrial regulatory and surveillance pathways (fission and fusion) or mitochondrial bioenergetics in response to injury. Furthermore, deletion of myocardial FtH did not affect cardiac function, assessed by measurement of left ventricular ejection fraction, on days 1, 7, and 21 post injury. To identify the modulated pathways providing cardiomyocyte protection coincident with FtH deletion, we performed unbiased transcriptomic analysis. We found that following injury, FtH deletion was associated with upregulation of several genes with anti-ferroptotic properties, including heme oxygenase-1 (HO-1) and the cystine/glutamate anti-porter (Slc7a11). These results suggested that HO-1 overexpression mitigates ferroptosis via upregulation of Slc7a11. Indeed, using transgenic mice with HO-1 overexpression, we demonstrate that overexpressed HO-1 is coupled with increased Slc7a11 expression. In conclusion, we demonstrate that following injury, myocardial FtH deletion leads to a compensatory upregulation in a number of anti-ferroptotic genes, including HO-1. Such HO-1 induction leads to overexpression of Slc7a11 and protects the heart against ischemia-reperfusion-mediated ferroptosis, preserves mitochondrial function, and overall function of the myocardium. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases 2.0)
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20 pages, 3363 KiB  
Article
Ferryl Hemoglobin and Heme Induce A1-Microglobulin in Hemorrhaged Atherosclerotic Lesions with Inhibitory Function against Hemoglobin and Lipid Oxidation
by Dávid Pethő, Tamás Gáll, Zoltán Hendrik, Annamária Nagy, Lívia Beke, Attila Péter Gergely, Gábor Méhes, Csaba Tóth, Magnus Gram, Bo Åkerström, György Balla and József Balla
Int. J. Mol. Sci. 2021, 22(13), 6668; https://doi.org/10.3390/ijms22136668 - 22 Jun 2021
Cited by 4 | Viewed by 2205
Abstract
Infiltration of red blood cells into atheromatous plaques and oxidation of hemoglobin (Hb) and lipoproteins are implicated in the pathogenesis of atherosclerosis. α1-microglobulin (A1M) is a radical-scavenging and heme-binding protein. In this work, we examined the origin and role of A1M [...] Read more.
Infiltration of red blood cells into atheromatous plaques and oxidation of hemoglobin (Hb) and lipoproteins are implicated in the pathogenesis of atherosclerosis. α1-microglobulin (A1M) is a radical-scavenging and heme-binding protein. In this work, we examined the origin and role of A1M in human atherosclerotic lesions. Using immunohistochemistry, we observed a significant A1M immunoreactivity in atheromas and hemorrhaged plaques of carotid arteries in smooth muscle cells (SMCs) and macrophages. The most prominent expression was detected in macrophages of organized hemorrhage. To reveal a possible inducer of A1M expression in ruptured lesions, we exposed aortic endothelial cells (ECs), SMCs and macrophages to heme, Oxy- and FerrylHb. Both heme and FerrylHb, but not OxyHb, upregulated A1M mRNA expression in all cell types. Importantly, only FerrylHb induced A1M protein secretion in aortic ECs, SMCs and macrophages. To assess the possible function of A1M in ruptured lesions, we analyzed Hb oxidation and heme-catalyzed lipid peroxidation in the presence of A1M. We showed that recombinant A1M markedly inhibited Hb oxidation and heme-driven oxidative modification of low-density lipoproteins as well plaque lipids derived from atheromas. These results demonstrate the presence of A1M in atherosclerotic plaques and suggest its induction by heme and FerrylHb in the resident cells. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases 2.0)
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Review

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16 pages, 999 KiB  
Review
Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside
by József Balla and Abolfazl Zarjou
Int. J. Mol. Sci. 2021, 22(15), 8174; https://doi.org/10.3390/ijms22158174 - 30 Jul 2021
Cited by 5 | Viewed by 3469
Abstract
With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can [...] Read more.
With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases 2.0)
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