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      Heme Oxygenase-1 Deletion Affects Stress Erythropoiesis

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          Abstract

          Background

          Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.

          Methodology/Principal Findings

          We used a transplant model to induce stress conditions. In irradiated recipients that received hmox +/− or hmox +/+ bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1 +-cells expressing TNF-α. In the spleens of mice that received hmox +/− cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1 +-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.

          Conclusions/Significance

          As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

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          Most cited references37

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          Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.

          The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress. The anti-inflammatory properties of heme oxygenase-1 may serve as a basis for this cytoprotection. We demonstrate here that carbon monoxide, a by-product of heme catabolism by heme oxygenase, mediates potent anti-inflammatory effects. Both in vivo and in vitro, carbon monoxide at low concentrations differentially and selectively inhibited the expression of lipopolysaccharide-induced pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-1beta and increased the lipopolysaccharide-induced expression of the anti-inflammatory cytokine interleukin-10. Carbon monoxide mediated these anti-inflammatory effects not through a guanylyl cyclase-cGMP or nitric oxide pathway, but instead through a pathway involving the mitogen-activated protein kinases. These data indicate the possibility that carbon monoxide may have an important protective function in inflammatory disease states and thus has potential therapeutic uses.
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            The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase.

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              Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis

              Heme oxygenase 1 (HO-1) inhibits apoptosis by regulating cellular prooxidant iron. We now show that there is an additional mechanism by which HO-1 inhibits apoptosis, namely by generating the gaseous molecule carbon monoxide (CO). Overexpression of HO-1, or induction of HO-1 expression by heme, protects endothelial cells (ECs) from apoptosis. When HO-1 enzymatic activity is blocked by tin protoporphyrin (SnPPIX) or the action of CO is inhibited by hemoglobin (Hb), HO-1 no longer prevents EC apoptosis while these reagents do not affect the antiapoptotic action of bcl-2. Exposure of ECs to exogenous CO, under inhibition of HO-1 activity by SnPPIX, substitutes HO-1 in preventing EC apoptosis. The mechanism of action of HO-1/CO is dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) signaling transduction pathway. Expression of HO-1 or exposure of ECs to exogenous CO enhanced p38 MAPK activation by TNF-α. Specific inhibition of p38 MAPK activation by the pyridinyl imidazol SB203580 or through overexpression of a p38 MAPK dominant negative mutant abrogated the antiapoptotic effect of HO-1. Taken together, these data demonstrate that the antiapoptotic effect of HO-1 in ECs is mediated by CO and more specifically via the activation of p38 MAPK by CO.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                31 May 2011
                : 6
                : 5
                : e20634
                Affiliations
                [1 ]Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America
                [2 ]Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California, United States of America
                University of Louisville, United States of America
                Author notes

                Conceived and designed the experiments: Y-AC SK CHC. Performed the experiments: Y-AC RL. Analyzed the data: Y-AC SK DKS CHC. Contributed reagents/materials/analysis tools: RJW. Wrote the paper: Y-AC SK CHC. Revised the manuscript: RJW.

                Article
                PONE-D-11-04068
                10.1371/journal.pone.0020634
                3105104
                21655188
                317fbde5-5a4a-41d5-9870-4f9f02dfc948
                Cao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 1 March 2011
                : 6 May 2011
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Biochemistry
                Proteins
                Hemoproteins
                Molecular Cell Biology
                Cellular Types
                Stem Cells
                Hematopoietic Stem Cells
                Medicine
                Hematology
                Hematopoiesis
                Red Cells

                Uncategorized
                Uncategorized

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