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Special Issue "Heme- and Hemoglobin Stress in Human Diseases"

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

Deadline for manuscript submissions: 30 April 2021.

Special Issue Editor

Prof. Dr. József Balla
Website
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 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

Manuscript Submission Information

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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 (15 papers)

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Research

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Open AccessArticle
Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia
Int. J. Mol. Sci. 2021, 22(3), 988; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22030988 - 20 Jan 2021
Abstract
Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance [...] Read more.
Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessArticle
The Providence Mutation (βK82D) in Human Hemoglobin Substantially Reduces βCysteine 93 Oxidation and Oxidative Stress in Endothelial Cells
Int. J. Mol. Sci. 2020, 21(24), 9453; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249453 - 11 Dec 2020
Abstract
The highly toxic oxidative transformation of hemoglobin (Hb) to the ferryl state (HbFe4+) is known to occur in both in vitro and in vivo settings. We recently constructed oxidatively stable human Hbs, based on the Hb Providence (βK82D) mutation in sickle [...] Read more.
The highly toxic oxidative transformation of hemoglobin (Hb) to the ferryl state (HbFe4+) is known to occur in both in vitro and in vivo settings. We recently constructed oxidatively stable human Hbs, based on the Hb Providence (βK82D) mutation in sickle cell Hb (βE6V/βK82D) and in a recombinant crosslinked Hb (rHb0.1/βK82D). Using High Resolution Accurate Mass (HRAM) mass spectrometry, we first quantified the degree of irreversible oxidation of βCys93 in these proteins, induced by hydrogen peroxide (H2O2), and compared it to their respective controls (HbA and HbS). Both Hbs containing the βK82D mutation showed considerably less cysteic acid formation, a byproduct of cysteine irreversible oxidation. Next, we performed a novel study aimed at exploring the impact of introducing βK82D containing Hbs on vascular endothelial redox homeostasis and energy metabolism. Incubation of the mutants carrying βK82D with endothelial cells resulted in altered bioenergetic function, by improving basal cellular glycolysis and glycolytic capacity. Treatment of cells with Hb variants containing βK82D resulted in lower heme oxygenase-1 and ferritin expressions, compared to native Hbs. We conclude that the presence of βK82D confers oxidative stability to Hb and adds significant resistance to oxidative toxicity. Therefore, we propose that βK82D is a potential gene-editing target in the treatment of sickle cell disease and in the design of safe and effective oxygen therapeutics. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessArticle
Heme-Induced Oxidation of Cysteine Groups of Myofilament Proteins Leads to Contractile Dysfunction of Permeabilized Human Skeletal Muscle Fibres
Int. J. Mol. Sci. 2020, 21(21), 8172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218172 - 31 Oct 2020
Cited by 1
Abstract
Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force [...] Read more.
Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessArticle
Heme Oxygenase 1 and 2 Differentially Regulate Glucose Metabolism and Adipose Tissue Mitochondrial Respiration: Implications for Metabolic Dysregulation
Int. J. Mol. Sci. 2020, 21(19), 7123; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197123 - 27 Sep 2020
Abstract
Heme oxygenase (HO) consists of inducible (HO-1) and constitutive (HO-2) isoforms that are encoded by Hmox1 and Hmox2 genes, respectively. As an anti-inflammatory and antioxidant molecule, HO participates in the development of metabolic diseases. Whether Hmox deficiency causes metabolic abnormalities under basal conditions [...] Read more.
Heme oxygenase (HO) consists of inducible (HO-1) and constitutive (HO-2) isoforms that are encoded by Hmox1 and Hmox2 genes, respectively. As an anti-inflammatory and antioxidant molecule, HO participates in the development of metabolic diseases. Whether Hmox deficiency causes metabolic abnormalities under basal conditions remains unclear. We hypothesized that HO-1 and HO-2 differentially affect global and adipose tissue metabolism. To test this hypothesis, we determined insulin sensitivity, glucose tolerance, energy expenditure, and respiratory exchange ratio in global Hmox1-/- and Hmox2-/- mice. Body weight was reduced in female but not male Hmox1-/- and Hmox2-/- mice. Reduced insulin sensitivity and physical activity were observed in Hmox1-/- but not Hmox2-/- mice. Deletion of either Hmox1 or Hmox2 had no effects on glucose tolerance, energy expenditure or respiratory exchange ratio. Mitochondrial respiration was unchanged in gonadal fat pads (white adipose tissue, WAT) of Hmox1-/- mice. Hmox2 deletion increased proton leak and glycolysis in gonadal, but not interscapular fat tissues (brown adipose tissue, BAT). Uncoupling protein and Hmox1 genes were unchanged in gonadal fat pads of Hmox2-/- mice. Conclusively, HO-1 maintains insulin sensitivity, while HO-2 represses glycolysis and proton leak in the WAT under basal condition. This suggests that HO-1 and HO-2 differentially modulate metabolism, which may impact the metabolic syndrome. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessArticle
Heme Oxygenase-1 Supports Mitochondrial Energy Production and Electron Transport Chain Activity in Cultured Lung Epithelial Cells
Int. J. Mol. Sci. 2020, 21(18), 6941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186941 - 22 Sep 2020
Abstract
Heme oxygenase-1 is induced by many cellular stressors and catalyzes the breakdown of heme to generate carbon monoxide and bilirubin, which confer cytoprotection. The role of HO-1 likely extends beyond the simple production of antioxidants, for example HO-1 activity has also been implicated [...] Read more.
Heme oxygenase-1 is induced by many cellular stressors and catalyzes the breakdown of heme to generate carbon monoxide and bilirubin, which confer cytoprotection. The role of HO-1 likely extends beyond the simple production of antioxidants, for example HO-1 activity has also been implicated in metabolism, but this function remains unclear. Here we used an HO-1 knockout lung cell line to further define the contribution of HO-1 to cellular metabolism. We found that knockout cells exhibit reduced growth and mitochondrial respiration, measured by oxygen consumption rate. Specifically, we found that HO-1 contributed to electron transport chain activity and utilization of certain mitochondrial fuels. Loss of HO-1 had no effect on intracellular non-heme iron concentration or on proteins whose levels and activities depend on available iron. We show that HO-1 supports essential functions of mitochondria, which highlights the protective effects of HO-1 in diverse pathologies and tissue types. Our results suggest that regulation of heme may be an equally significant role of HO-1. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessArticle
α1-Microglobulin (A1M) Protects Human Proximal Tubule Epithelial Cells from Heme-Induced Damage In Vitro
Int. J. Mol. Sci. 2020, 21(16), 5825; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165825 - 13 Aug 2020
Cited by 4
Abstract
Oxidative stress is associated with many renal disorders, both acute and chronic, and has also been described to contribute to the disease progression. Therefore, oxidative stress is a potential therapeutic target. The human antioxidant α1-microglobulin (A1M) is a plasma and tissue [...] Read more.
Oxidative stress is associated with many renal disorders, both acute and chronic, and has also been described to contribute to the disease progression. Therefore, oxidative stress is a potential therapeutic target. The human antioxidant α1-microglobulin (A1M) is a plasma and tissue protein with heme-binding, radical-scavenging and reductase activities. A1M can be internalized by cells, localized to the mitochondria and protect mitochondrial function. Due to its small size, A1M is filtered from the blood into the glomeruli, and taken up by the renal tubular epithelial cells. A1M has previously been described to reduce renal damage in animal models of preeclampsia, radiotherapy and rhabdomyolysis, and is proposed as a pharmacological agent for the treatment of kidney damage. In this paper, we examined the in vitro protective effects of recombinant human A1M (rA1M) in human proximal tubule epithelial cells. Moreover, rA1M was found to protect against heme-induced cell-death both in primary cells (RPTEC) and in a cell-line (HK-2). Expression of stress-related genes was upregulated in both cell cultures in response to heme exposure, as measured by qPCR and confirmed with in situ hybridization in HK-2 cells, whereas co-treatment with rA1M counteracted the upregulation. Mitochondrial respiration, analyzed with the Seahorse extracellular flux analyzer, was compromised following exposure to heme, but preserved by co-treatment with rA1M. Finally, heme addition to RPTE cells induced an upregulation of the endogenous cellular expression of A1M, via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-pathway. Overall, data suggest that A1M/rA1M protects against stress-induced damage to tubule epithelial cells that, at least partly, can be attributed to maintaining mitochondrial function. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessArticle
Heme Oxygenase Protects against Placental Vascular Inflammation and Abortion by the Alarmin Heme in Mice
Int. J. Mol. Sci. 2020, 21(15), 5385; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155385 - 29 Jul 2020
Abstract
Both infectious as non-infectious inflammation can cause placental dysfunction and pregnancy complications. During the first trimester of human gestation, when palatogenesis takes place, intrauterine hematoma and hemorrhage are common phenomena, causing the release of large amounts of heme, a well-known alarmin. We postulated [...] Read more.
Both infectious as non-infectious inflammation can cause placental dysfunction and pregnancy complications. During the first trimester of human gestation, when palatogenesis takes place, intrauterine hematoma and hemorrhage are common phenomena, causing the release of large amounts of heme, a well-known alarmin. We postulated that exposure of pregnant mice to heme during palatogenesis would initiate oxidative and inflammatory stress, leading to pathological pregnancy, increasing the incidence of palatal clefting and abortion. Both heme oxygenase isoforms (HO-1 and HO-2) break down heme, thereby generating anti-oxidative and -inflammatory products. HO may thus counteract these heme-induced injurious stresses. To test this hypothesis, we administered heme to pregnant CD1 outbred mice at Day E12 by intraperitoneal injection in increasing doses: 30, 75 or 150 μmol/kg body weight (30H, 75H or 150H) in the presence or absence of HO-activity inhibitor SnMP from Day E11. Exposure to heme resulted in a dose-dependent increase in abortion. At 75H half of the fetuses where resorbed, while at 150H all fetuses were aborted. HO-activity protected against heme-induced abortion since inhibition of HO-activity aggravated heme-induced detrimental effects. The fetuses surviving heme administration demonstrated normal palatal fusion. Immunostainings at Day E16 demonstrated higher numbers of ICAM-1 positive blood vessels, macrophages and HO-1 positive cells in placenta after administration of 75H or SnMP + 30H. Summarizing, heme acts as an endogenous “alarmin” during pregnancy in a dose-dependent fashion, while HO-activity protects against heme-induced placental vascular inflammation and abortion. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessArticle
The Fungal Iron Chelator Desferricoprogen Inhibits Atherosclerotic Plaque Formation
Int. J. Mol. Sci. 2020, 21(13), 4746; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134746 - 03 Jul 2020
Abstract
Hemoglobin, heme and iron are implicated in the progression of atherosclerosis. Therefore, we investigated whether the hydrophobic fungal iron chelator siderophore, desferricoprogen (DFC) inhibits atherosclerosis. DFC reduced atherosclerotic plaque formation in ApoE−/− mice on an atherogenic diet. It lowered the plasma level [...] Read more.
Hemoglobin, heme and iron are implicated in the progression of atherosclerosis. Therefore, we investigated whether the hydrophobic fungal iron chelator siderophore, desferricoprogen (DFC) inhibits atherosclerosis. DFC reduced atherosclerotic plaque formation in ApoE−/− mice on an atherogenic diet. It lowered the plasma level of oxidized LDL (oxLDL) and inhibited lipid peroxidation in aortic roots. The elevated collagen/elastin content and enhanced expression of adhesion molecule VCAM-1 were decreased. DFC diminished oxidation of Low-density Lipoprotein (LDL) and plaque lipids catalyzed by heme or hemoglobin. Formation of foam cells, uptake of oxLDL by macrophages, upregulation of CD36 and increased expression of TNF-α were reduced by DFC in macrophages. TNF-triggered endothelial cell activation (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecules (ICAMs), E-selectin) and increased adhesion of monocytes to endothelium were attenuated. The increased endothelial permeability and intracellular gap formation provoked by TNF-α was also prevented by DFC. DFC acted as a cytoprotectant in endothelial cells and macrophages challenged with a lethal dose of oxLDL and lowered the expression of stress-responsive heme oxygenase-1 as sublethal dose was employed. Saturation of desferrisiderophore with iron led to the loss of the beneficial effects. We demonstrated that DFC accumulated within the atheromas of the aorta in ApoE−/− mice. DFC represents a novel therapeutic approach to control the progression of atherosclerosis. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Review

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Open AccessReview
Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models
Int. J. Mol. Sci. 2021, 22(4), 1514; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041514 - 03 Feb 2021
Abstract
Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 [...] Read more.
Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessReview
The Role of Haptoglobin Polymorphism in Cardiovascular Disease in the Setting of Diabetes
Int. J. Mol. Sci. 2021, 22(1), 287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010287 - 30 Dec 2020
Abstract
Atherosclerotic cardiovascular disease (CVD) is the major cause of morbidity and mortality in individuals with diabetes mellitus (DM). Preclinical models have suggested that excessive oxidative stress and hyperglycemia are directly responsible for this pathological association. However, numerous clinical trials involving the administration of [...] Read more.
Atherosclerotic cardiovascular disease (CVD) is the major cause of morbidity and mortality in individuals with diabetes mellitus (DM). Preclinical models have suggested that excessive oxidative stress and hyperglycemia are directly responsible for this pathological association. However, numerous clinical trials involving the administration of high doses of the antioxidant vitamin E or attempts at strict glycemic control have failed to show a significant reduction of CVD in DM patients. We describe here a possible explanation for the failure of these trials, that being their lack of proper patient selection. The haptoglobin (Hp) genotype is a major determinant of the risk of CVD in the setting of DM. Treatment of individuals with the high-risk Hp genotype with antioxidants or aggressive glycemic control has shown benefit in several small studies. These studies suggest a precision medicine-based approach to preventing diabetes complications. This approach would have a profound effect on the costs of diabetes care and could dramatically reduce morbidity from diabetes. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessReview
Therapeutic Potential of Carbon Monoxide (CO) and Hydrogen Sulfide (H2S) in Hemolytic and Hemorrhagic Vascular Disorders—Interaction between the Heme Oxygenase and H2S-Producing Systems
Int. J. Mol. Sci. 2021, 22(1), 47; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010047 - 23 Dec 2020
Abstract
Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with [...] Read more.
Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with inflammatory response, reprogramming of cellular metabolism, differentiation, stress, and even death. Here, we discuss these cellular responses with particular focus on their mechanisms that are linked to the pathological consequences of hemorrhage and hemolysis. In recent years, endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H2S), have gained a lot of interest in connection with various human pathologies. Thus, many CO and H2S-releasing molecules have been developed and applied in various human disorders, including hemolytic and hemorrhagic diseases. Here, we discuss our current understanding of oxidized hemoglobin and heme-induced cell and tissue damage with particular focus on inflammation, cellular metabolism and differentiation, and endoplasmic reticulum stress in hemolytic/hemorrhagic human diseases, and the potential beneficial role of CO and H2S in these pathologies. More detailed mechanistic insights into the complex pathology of hemolytic/hemorrhagic diseases through heme oxygenase-1/CO as well as H2S pathways would reveal new therapeutic approaches that can be exploited for clinical benefit. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessReview
Heme Degradation in Pathophysiology of and Countermeasures to Inflammation-Associated Disease
Int. J. Mol. Sci. 2020, 21(24), 9698; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249698 - 18 Dec 2020
Abstract
The class of tetrapyrrol “coordination complexes” called hemes are prosthetic group components of metalloproteins including hemoglobin, which provide functionality to these physiologically essential macromolecules by reversibly binding diatomic gasses, notably O2, which complexes to ferrous (reduced/Fe(II)) iron within the heme porphyrin [...] Read more.
The class of tetrapyrrol “coordination complexes” called hemes are prosthetic group components of metalloproteins including hemoglobin, which provide functionality to these physiologically essential macromolecules by reversibly binding diatomic gasses, notably O2, which complexes to ferrous (reduced/Fe(II)) iron within the heme porphyrin ring of hemoglobin in a pH- and PCO2-dependent manner—thus allowing their transport and delivery to anatomic sites of their function. Here, pathologies associated with aberrant heme degradation are explored in the context of their underlying mechanisms and emerging medical countermeasures developed using heme oxygenase (HO), its major degradative enzyme and bioactive metabolites produced by HO activity. Tissue deposits of heme accumulate as a result of the removal of senescent or damaged erythrocytes from circulation by splenic macrophages, which destroy the cells and internal proteins, including hemoglobin, leaving free heme to accumulate, posing a significant toxicogenic challenge. In humans, HO uses NADPH as a reducing agent, along with molecular oxygen, to degrade heme into carbon monoxide (CO), free ferrous iron (FeII), which is sequestered by ferritin protein, and biliverdin, subsequently metabolized to bilirubin, a potent inhibitor of oxidative stress-mediated tissue damage. CO acts as a cellular messenger and augments vasodilation. Nevertheless, disease- or trauma-associated oxidative stressors sufficiently intense to overwhelm HO may trigger or exacerbate a wide range of diseases, including cardiovascular and neurologic syndromes. Here, strategies are described for counteracting the effects of aberrant heme degradation, with a particular focus on “bioflavonoids” as HO inducers, shown to cause amelioration of severe inflammatory diseases. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessReview
The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis—Therapeutic Opportunities in Hemolytic Conditions
Int. J. Mol. Sci. 2020, 21(19), 7234; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197234 - 30 Sep 2020
Cited by 2
Abstract
α1-microglobulin (A1M) is a small protein present in vertebrates including humans. It has several physiologically relevant properties, including binding of heme and radicals as well as enzymatic reduction, that are used in the protection of cells and tissue. Research has revealed [...] Read more.
α1-microglobulin (A1M) is a small protein present in vertebrates including humans. It has several physiologically relevant properties, including binding of heme and radicals as well as enzymatic reduction, that are used in the protection of cells and tissue. Research has revealed that A1M can ameliorate heme and ROS-induced injuries in cell cultures, organs, explants and animal models. Recently, it was shown that A1M could reduce hemolysis in vitro, observed with several different types of insults and sources of RBCs. In addition, in a recently published study, it was observed that mice lacking A1M (A1M-KO) developed a macrocytic anemia phenotype. Altogether, this suggests that A1M may have a role in RBC development, stability and turnover. This opens up the possibility of utilizing A1M for therapeutic purposes in pathological conditions involving erythropoietic and hemolytic abnormalities. Here, we provide an overview of A1M and its potential therapeutic effect in the context of the following erythropoietic and hemolytic conditions: Diamond-Blackfan anemia (DBA), 5q-minus myelodysplastic syndrome (5q-MDS), blood transfusions (including storage), intraventricular hemorrhage (IVH), preeclampsia (PE) and atherosclerosis. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessReview
Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases
Int. J. Mol. Sci. 2020, 21(18), 6756; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186756 - 15 Sep 2020
Cited by 2
Abstract
As the main particulate component of the circulating blood, RBCs play major roles in physiological hemodynamics and impact all arterial wall pathologies. RBCs are the main determinant of blood viscosity, defining the frictional forces exerted by the blood on the arterial wall. This [...] Read more.
As the main particulate component of the circulating blood, RBCs play major roles in physiological hemodynamics and impact all arterial wall pathologies. RBCs are the main determinant of blood viscosity, defining the frictional forces exerted by the blood on the arterial wall. This function is used in phylogeny and ontogeny of the cardiovascular (CV) system, allowing the acquisition of vasomotricity adapted to local metabolic demands, and systemic arterial pressure after birth. In pathology, RBCs collide with the arterial wall, inducing both local retention of their membranous lipids and local hemolysis, releasing heme-Fe++ with a high toxicity for arterial cells: endothelial and smooth muscle cells (SMCs) cardiomyocytes, neurons, etc. Specifically, overloading of cells by Fe++ promotes cell death. This local hemolysis is an event associated with early and advanced stages of human atherosclerosis. Similarly, the permanent renewal of mural RBC clotting is the major support of oxidation in abdominal aortic aneurysm. In parallel, calcifications promote intramural hemorrhages, and hemorrhages promote an osteoblastic phenotypic shift of arterial wall cells. Different plasma or tissue systems are able, at least in part, to limit this injury by acting at the different levels of this system. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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Open AccessReview
Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis
Int. J. Mol. Sci. 2020, 21(12), 4259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124259 - 15 Jun 2020
Cited by 3
Abstract
Mid-life stage adults are at higher risk of developing venous thrombosis (VT)/thromboembolism (VT/E). Aging is characterized by an overproduction of reactive oxygen species (ROS), which could evoke a series of physiological changes involved in thrombosis. Here, we focus on the critical role of [...] Read more.
Mid-life stage adults are at higher risk of developing venous thrombosis (VT)/thromboembolism (VT/E). Aging is characterized by an overproduction of reactive oxygen species (ROS), which could evoke a series of physiological changes involved in thrombosis. Here, we focus on the critical role of ROS within the red blood cell (RBC) in initiating venous thrombosis during aging. Growing evidence has shifted our interest in the role of unjustifiably unvalued RBCs in blood coagulation. RBCs can be a major source of oxidative stress during aging, since RBC redox homeostasis is generally compromised due to the discrepancy between prooxidants and antioxidants. As a result, ROS accumulate within the RBC due to the constant endogenous hemoglobin (Hb) autoxidation and NADPH oxidase activation, and the uptake of extracellular ROS released by other cells in the circulation. The elevated RBC ROS level affects the RBC membrane structure and function, causing loss of membrane integrity, and decreased deformability. These changes impair RBC function in hemostasis and thrombosis, favoring a hypercoagulable state through enhanced RBC aggregation, RBC binding to endothelial cells affecting nitric oxide availability, RBC-induced platelet activation consequently modulating their activity, RBC interaction with and activation of coagulation factors, increased RBC phosphatidylserine exposure and release of microvesicles, accelerated aging and hemolysis. Thus, RBC oxidative stress during aging typifies an ultimate mechanism in system failure, which can affect major processes involved in the development of venous thrombosis in a variety of ways. The reevaluated concept of the critical role of RBC ROS in the activation of thrombotic events during aging will help identify potential targets for novel strategies to prevent/reduce the risk for VT/E or VT/E recurrences in mid-life stage adults. Full article
(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)
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