International Journal of Molecular Sciences

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22 pages, 3122 KiB

Open AccessArticle

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

by Karolina Bukowska-Strakova, Joanna Włodek, Ewelina Pitera, Magdalena Kozakowska, Anna Konturek-Cieśla, Maciej Cieśla, Monika Gońka, Witold Nowak, Aleksandra Wieczorek, Katarzyna Pawińska-Wąsikowska, Alicja Józkowicz and Maciej Siedlar

Int. J. Mol. Sci. 2021, 22(3), 988; https://doi.org/10.3390/ijms22030988 - 20 Jan 2021

Cited by 10 | Viewed by 3210

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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15 pages, 2114 KiB

Open AccessArticle

The Providence Mutation (βK82D) in Human Hemoglobin Substantially Reduces βCysteine 93 Oxidation and Oxidative Stress in Endothelial Cells

by Sirsendu Jana, Michael Brad Strader and Abdu I. Alayash

Int. J. Mol. Sci. 2020, 21(24), 9453; https://doi.org/10.3390/ijms21249453 - 11 Dec 2020

Cited by 7 | Viewed by 2492

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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17 pages, 1704 KiB

Open AccessArticle

Heme-Induced Oxidation of Cysteine Groups of Myofilament Proteins Leads to Contractile Dysfunction of Permeabilized Human Skeletal Muscle Fibres

by Gerardo Alvarado, Attila Tóth, Éva Csősz, Gergő Kalló, Katalin Dankó, Zoltán Csernátony, Ann Smith, Magnus Gram, Bo Akerström, István Édes, György Balla, Zoltán Papp and József Balla

Int. J. Mol. Sci. 2020, 21(21), 8172; https://doi.org/10.3390/ijms21218172 - 31 Oct 2020

Cited by 5 | Viewed by 2716

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 (F_o) by about 50% and evoked an approximately 3-fold increase in Ca²⁺-independent (passive) force (F_passive). 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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14 pages, 1638 KiB

Open AccessArticle

Heme Oxygenase 1 and 2 Differentially Regulate Glucose Metabolism and Adipose Tissue Mitochondrial Respiration: Implications for Metabolic Dysregulation

by Hongwei Yao, Abigail L. Peterson, Jie Li, Haiyan Xu and Phyllis A. Dennery

Int. J. Mol. Sci. 2020, 21(19), 7123; https://doi.org/10.3390/ijms21197123 - 27 Sep 2020

Cited by 14 | Viewed by 3021

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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11 pages, 1659 KiB

Open AccessArticle

Heme Oxygenase-1 Supports Mitochondrial Energy Production and Electron Transport Chain Activity in Cultured Lung Epithelial Cells

by Jennifer F. Carr, David Garcia, Alejandro Scaffa, Abigail L. Peterson, Andrew J. Ghio and Phyllis A. Dennery

Int. J. Mol. Sci. 2020, 21(18), 6941; https://doi.org/10.3390/ijms21186941 - 22 Sep 2020

Cited by 16 | Viewed by 3419

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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16 pages, 3254 KiB

Open AccessArticle

α₁-Microglobulin (A1M) Protects Human Proximal Tubule Epithelial Cells from Heme-Induced Damage In Vitro

by Amanda Kristiansson, Sara Davidsson, Maria E. Johansson, Sarah Piel, Eskil Elmér, Magnus J. Hansson, Bo Åkerström and Magnus Gram

Int. J. Mol. Sci. 2020, 21(16), 5825; https://doi.org/10.3390/ijms21165825 - 13 Aug 2020

Cited by 21 | Viewed by 3907

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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20 pages, 3138 KiB

Open AccessArticle

Heme Oxygenase Protects against Placental Vascular Inflammation and Abortion by the Alarmin Heme in Mice

by Christiaan M. Suttorp, René E. M. van Rheden, Natasja W. M. van Dijk, Maria P. A. C. Helmich, Anne Marie Kuijpers-Jagtman and Frank A. D. T. G. Wagener

Int. J. Mol. Sci. 2020, 21(15), 5385; https://doi.org/10.3390/ijms21155385 - 29 Jul 2020

Cited by 1 | Viewed by 4902

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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24 pages, 3097 KiB

Open AccessArticle

The Fungal Iron Chelator Desferricoprogen Inhibits Atherosclerotic Plaque Formation

by László Potor, Katalin Éva Sikura, Hajnalka Hegedűs, Dávid Pethő, Zsuzsa Szabó, Zsuzsa M Szigeti, István Pócsi, György Trencsényi, Dezső Szikra, Ildikó Garai, Tamás Gáll, Zsolt Combi, János Kappelmayer, György Balla and József Balla

Int. J. Mol. Sci. 2020, 21(13), 4746; https://doi.org/10.3390/ijms21134746 - 3 Jul 2020

Cited by 9 | Viewed by 3711

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

Jump to: Research

23 pages, 1240 KiB

Open AccessReview

Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders

by Stefan W. Ryter

Int. J. Mol. Sci. 2021, 22(11), 5509; https://doi.org/10.3390/ijms22115509 - 24 May 2021

Cited by 27 | Viewed by 7917

Abstract

The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote [...] Read more.

The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases. Full article

(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)

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24 pages, 325 KiB

Open AccessReview

When the Blood Hits Your Brain: The Neurotoxicity of Extravasated Blood

by Jesse A. Stokum, Gregory J. Cannarsa, Aaron P. Wessell, Phelan Shea, Nicole Wenger and J. Marc Simard

Int. J. Mol. Sci. 2021, 22(10), 5132; https://doi.org/10.3390/ijms22105132 - 12 May 2021

Cited by 31 | Viewed by 4386

Abstract

Hemorrhage in the central nervous system (CNS), including intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and aneurysmal subarachnoid hemorrhage (aSAH), remains highly morbid. Trials of medical management for these conditions over recent decades have been largely unsuccessful in improving outcome and reducing mortality. Beyond [...] Read more.

Hemorrhage in the central nervous system (CNS), including intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and aneurysmal subarachnoid hemorrhage (aSAH), remains highly morbid. Trials of medical management for these conditions over recent decades have been largely unsuccessful in improving outcome and reducing mortality. Beyond its role in creating mass effect, the presence of extravasated blood in patients with CNS hemorrhage is generally overlooked. Since trials of surgical intervention to remove CNS hemorrhage have been generally unsuccessful, the potent neurotoxicity of blood is generally viewed as a basic scientific curiosity rather than a clinically meaningful factor. In this review, we evaluate the direct role of blood as a neurotoxin and its subsequent clinical relevance. We first describe the molecular mechanisms of blood neurotoxicity. We then evaluate the clinical literature that directly relates to the evacuation of CNS hemorrhage. We posit that the efficacy of clot removal is a critical factor in outcome following surgical intervention. Future interventions for CNS hemorrhage should be guided by the principle that blood is exquisitely toxic to the brain. Full article

(This article belongs to the Special Issue Heme- and Hemoglobin Stress in Human Diseases)

16 pages, 1844 KiB

Open AccessReview

Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

by Akihiro Yachie

Int. J. Mol. Sci. 2021, 22(4), 1514; https://doi.org/10.3390/ijms22041514 - 3 Feb 2021

Cited by 57 | Viewed by 6925

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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10 pages, 354 KiB

Open AccessReview

The Role of Haptoglobin Polymorphism in Cardiovascular Disease in the Setting of Diabetes

by Shmuel Somer and Andrew P. Levy

Int. J. Mol. Sci. 2021, 22(1), 287; https://doi.org/10.3390/ijms22010287 - 30 Dec 2020

Cited by 11 | Viewed by 3411

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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24 pages, 2986 KiB

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

by Tamás Gáll, Dávid Pethő, Annamária Nagy, György Balla and József Balla

Int. J. Mol. Sci. 2021, 22(1), 47; https://doi.org/10.3390/ijms22010047 - 23 Dec 2020

Cited by 8 | Viewed by 4300

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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25 pages, 1309 KiB

Open AccessReview

Heme Degradation in Pathophysiology of and Countermeasures to Inflammation-Associated Disease

by Donald David Haines and Arpad Tosaki

Int. J. Mol. Sci. 2020, 21(24), 9698; https://doi.org/10.3390/ijms21249698 - 18 Dec 2020

Cited by 30 | Viewed by 7431

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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21 pages, 2945 KiB

Open AccessReview

The Role of α₁-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis—Therapeutic Opportunities in Hemolytic Conditions

by Amanda Kristiansson, Magnus Gram, Johan Flygare, Stefan R. Hansson, Bo Åkerström and Jill R. Storry

Int. J. Mol. Sci. 2020, 21(19), 7234; https://doi.org/10.3390/ijms21197234 - 30 Sep 2020

Cited by 19 | Viewed by 3767

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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20 pages, 2484 KiB

Open AccessReview

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

by Jean-Baptiste Michel and José Luis Martin-Ventura

Int. J. Mol. Sci. 2020, 21(18), 6756; https://doi.org/10.3390/ijms21186756 - 15 Sep 2020

Cited by 45 | Viewed by 7608

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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Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

by Qinhong Wang and Rahima Zennadi

Int. J. Mol. Sci. 2020, 21(12), 4259; https://doi.org/10.3390/ijms21124259 - 15 Jun 2020

Cited by 74 | Viewed by 9693

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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