Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

Nagababu, Enika; Fabry, Mary E.; Nagel, Ronald L.; Rifkind, Joseph M.

doi:10.1016/j.bcmd.2007.12.003

Cited by 103 publications

(83 citation statements)

References 30 publications

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“…The role of H 2 O 2 in E-selectin expression was examined further in the lungs of mice (Hb mut ) expressing an Hb mutation that causes Hb instability and decreased oxygen affinity to Hb (24,25), thereby increasing hypoxia-induced Hb autoxidation and H 2 O 2 production (16,17). Our previous findings indicate that in lungs of Hb mut mice, hypoxia increases erythrocyteendothelial H 2 O 2 transfer as well as Ca 21 -dependent endothelial P-selectin expression (20).…”

Section: Hypoxia Causes Erythrocyte-derived H 2 O 2 Proinflammatory Ementioning

confidence: 99%

Erythrocytes Induce Proinflammatory Endothelial Activation in Hypoxia

Huertas

Das²,

Emin³

et al. 2013

Am J Respir Cell Mol Biol

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Although exposure to ambient hypoxia is known to cause proinflammatory vascular responses, the mechanisms initiating these responses are not understood. We tested the hypothesis that in systemic hypoxia, erythrocyte-derived H 2 O 2 induces proinflammatory gene transcription in vascular endothelium. We exposed mice or isolated, perfused murine lungs to 4 hours of hypoxia (8% O 2 ). Leukocyte counts increased in the bronchoalveolar lavage. The expression of leukocyte adhesion receptors, reactive oxygen species, and protein tyrosine phosphorylation increased in freshly recovered lung endothelial cells (FLECs). These effects were inhibited by extracellular catalase and by the removal of erythrocytes, indicating that the responses were attributable to erythrocyte-derived H 2 O 2 . Concomitant nuclear translocation of the p65 subunit of NF-kB and hypoxiainducible factor-1a stabilization in FLECs occurred only in the presence of erythrocytes. Hemoglobin binding to the erythrocyte membrane protein, band 3, induced the release of H 2 O 2 from erythrocytes and the p65 translocation in FLECs. These data indicate for the first time, to our knowledge, that erythrocytes are responsible for endothelial transcriptional responses in hypoxia.Keywords: hypoxia; erythrocytes; endothelium; lung; inflammation Systemic hypoxia, which is characterized by a decrease in the partial pressure of oxygen in blood (PO 2 ), results from a lack of oxygen in inhaled breath, or from impaired blood oxygenation because of lung disease. The circulatory response to a decrease of PO 2 is best characterized by pulmonary arterial vasoconstriction, a protective strategy that redistributes the pulmonary blood flow from hypoxic to well-ventilated regions of the lung. An additional vascular effect may involve a hypoxia-induced innate immune response, characterized by leukocyte activation and tissue injury (1). However, this effect remains controversial. Support for the immune effect derives from evidence in animal models that ambient hypoxia causes lung injury (2-5), systemic inflammation (4, 5), and vascular leakage (2, 6). A 4-hour exposure to 8% O 2 in mice activates NF-kB in astrocytes and hepatocytes (7), suggesting that hypoxia-induced proinflammatory gene transcription occurs in these cells.The evidence opposing the hypoxic immune response comes from lung lymph flow studies in adult sheep. According to these studies, ambient hypoxia does not increase lung microvascular permeability to proteins, and it does not cause pulmonary edema (8, 9). The clinical evidence for the hypoxic immune effect is mixed, and is based on studies of high-altitude pulmonary edema (HAPE), a form of lung injury that follows exposure to hypoxia at high altitude. Radioactive tracer studies in patients with HAPE confirm the sheep data insofar as lung microvascular permeability does not increase (10). Several studies indicate that the bronchoalveolar lavage (BAL) of patients with HAPE is enriched in leukocytes, proteins, and proinflammatory factors, indicating that HAPE causes lu...

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Section: Hypoxia Causes Erythrocyte-derived H 2 O 2 Proinflammatory Ementioning

confidence: 99%

Erythrocytes Induce Proinflammatory Endothelial Activation in Hypoxia

Huertas

Das²,

Emin³

et al. 2013

Am J Respir Cell Mol Biol

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“…As previously noted, free α-globin is a highly unstable molecule and when devoid of stabilizing binding partners, forms large insoluble aggregates which can be visualized by light microscopy in an estimated one third of erythroid progenitor cells. 65 Much of the excess α-globin undergoes auto-oxidation to produce equal molar ratios of metHb and superoxide 66 which can lead to an autocatalytic oxidative process in the cell. The oxidized ferric iron is bound more loosely to α-globin compared to the ferrous form which results in degradation of haem 67 and ultimately the release of iron which lodges in the cell membrane.…”

Section: Cellular Consequences Of Excess α α-Globin Chainsmentioning

confidence: 99%

“…The oxidized ferric iron is bound more loosely to α-globin compared to the ferrous form which results in degradation of haem 67 and ultimately the release of iron which lodges in the cell membrane. 66,68 In addition, oxidized haem-containing α-globin is also found bound to the cytoskeleton. 64,69,70 In this unstable conformation, both the haem group and the iron are able to participate in redox reactions leading to generation of ROS which can then oxidize adjacent membrane proteins.…”

Section: Cellular Consequences Of Excess α α-Globin Chainsmentioning

confidence: 99%

“…71 In addition, erythrocytes in peripheral circulation also bind increased levels of IgG. 66 Under normal conditions, IgG typically binds senescent cell antigens to signal macrophage removal, 72,73 but in β-thalassemia, this process appears accelerated by the accumulated oxidative stress and subsequent haem degradation and membrane damage. 66 Thus, the excess α-globin in β-thalassemia generates high levels of ROS in an autocatalytic process which most likely leads to premature apoptosis in the bone marrow and ineffective erythropoiesis.…”

Section: Cellular Consequences Of Excess α α-Globin Chainsmentioning

confidence: 99%

“…66 Under normal conditions, IgG typically binds senescent cell antigens to signal macrophage removal, 72,73 but in β-thalassemia, this process appears accelerated by the accumulated oxidative stress and subsequent haem degradation and membrane damage. 66 Thus, the excess α-globin in β-thalassemia generates high levels of ROS in an autocatalytic process which most likely leads to premature apoptosis in the bone marrow and ineffective erythropoiesis. In addition, red cells which survive to reach the circulation continue to be subjected to high levels of oxidative stress leading to structural abnormalities of the cytoskeleton and hemolysis or alternatively, accelerated senescence and macrophage clearance.…”

Section: Cellular Consequences Of Excess α α-Globin Chainsmentioning

confidence: 99%

See 2 more Smart Citations

Controlling -globin: a review of -globin expression and its impact on -thalassemia

Voon¹,

Vadolas²

2008

Haematologica

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Synthesis of α-globin and α-globin subunits of hemoglobin occurs at high levels during erythrocyte differentiation in a tightly controlled and co-ordinated fashion. Expression of α-globin is a fascinatingly complex process which has been meticulously defined in several recent studies, from chromatin modifications to Pol II recruitment. Following this, α-globin transcripts are processed and stabilized by a protein complex which binds the 3' untranslated region. Transcription and stabilization contribute to high level expression of α-globin. However, translation of α-globin at levels exceeding α-globin expression damages cellular membranes and results in β-thalassemia. It is, therefore, crucial that α-globin proteins are properly folded and stabilized, processes which are dependent on the presence of haem and AHSP. The exceedingly well-characterized process of α-globin expression elegantly illustrates the complex interaction of factors which are required to balance necessary high expression against the negative impacts of overexpression.

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Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management

et al. 2011

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the CURAMA Study GroupSickle cell disease (SCD) is a hemoglobinopathy characterized by hemolytic anemia, increased susceptibility to infections and vaso-occlusion leading to a reduced quality of life and life expectancy. Oxidative stress is an important feature of SCD and plays a significant role in the pathophysiology of hemolysis, vaso-occlusion and ensuing organ damage in sickle cell patients. Reactive oxygen species (ROS) and the (end-)products of their oxidative reactions are potential markers of disease severity and could be targets for antioxidant therapies. This review will summarize the role of ROS in SCD and their potential implication for SCD management. Am. J. Hematol. 86:484-489, 2011. V

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Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

Cited by 103 publications

References 30 publications

Erythrocytes Induce Proinflammatory Endothelial Activation in Hypoxia

Erythrocytes Induce Proinflammatory Endothelial Activation in Hypoxia

Controlling -globin: a review of -globin expression and its impact on -thalassemia

Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management

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