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Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model
Aims: Release of large amounts of free heme into circulation, overproduction of reactive oxygen species (ROS), and activation of toll-like receptor-4-dependent responses are considered critical for the ability of heme to promote oxidative stress and to initiate proinflammatory responses, posing a se...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mary Ann Liebert, Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034398/ https://www.ncbi.nlm.nih.gov/pubmed/29212341 http://dx.doi.org/10.1089/ars.2017.7089 |
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author | Tangudu, Naveen Kumar Alan, Betül Vinchi, Francesca Wörle, Katharina Lai, Dilay Vettorazzi, Sabine Leopold, Kerstin Vujić Spasić, Maja |
author_facet | Tangudu, Naveen Kumar Alan, Betül Vinchi, Francesca Wörle, Katharina Lai, Dilay Vettorazzi, Sabine Leopold, Kerstin Vujić Spasić, Maja |
author_sort | Tangudu, Naveen Kumar |
collection | PubMed |
description | Aims: Release of large amounts of free heme into circulation, overproduction of reactive oxygen species (ROS), and activation of toll-like receptor-4-dependent responses are considered critical for the ability of heme to promote oxidative stress and to initiate proinflammatory responses, posing a serious threat to the body. A deep understanding of the consequences of heme overload on the regulation of cellular and systemic iron homeostasis is, however, still lacking. Results: The effects of heme on iron metabolism were studied in primary macrophages and in mouse models of acute and chronic hemolysis. We demonstrated that hemolysis was associated with a significant depletion of intracellular iron levels and increased expression of the sole iron exporter protein, ferroportin. The pathophysiological relevance of this mechanism was further demonstrated in sickle cell anemia mice, which, despite chronic hemolysis, maintained high ferroportin expression and increased iron export. We identified a redox active iron species and superoxide as regulators for ferroportin induction by heme. Scavenging the ROS production, by use of a pharmacological antioxidant N-acetylcysteine, prevented ferroportin induction and normalized intracellular iron levels in macrophages and in experimentally induced hemolysis in mice. Innovation: Our data propose that scavenging ROS levels may be a novel therapeutic strategy to balance intracellular iron levels and systemic iron influx in conditions associated with heme overload. Conclusion: This study identifies that the pro-oxidant, and not the proinflammatory, actions of heme profoundly impact on iron homeostasis by critically regulating the expression of ferroportin and iron export in hemolytic conditions. Antioxid. Redox Signal. 29, 484–499. |
format | Online Article Text |
id | pubmed-6034398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Mary Ann Liebert, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60343982018-08-10 Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model Tangudu, Naveen Kumar Alan, Betül Vinchi, Francesca Wörle, Katharina Lai, Dilay Vettorazzi, Sabine Leopold, Kerstin Vujić Spasić, Maja Antioxid Redox Signal Original Research Communications Aims: Release of large amounts of free heme into circulation, overproduction of reactive oxygen species (ROS), and activation of toll-like receptor-4-dependent responses are considered critical for the ability of heme to promote oxidative stress and to initiate proinflammatory responses, posing a serious threat to the body. A deep understanding of the consequences of heme overload on the regulation of cellular and systemic iron homeostasis is, however, still lacking. Results: The effects of heme on iron metabolism were studied in primary macrophages and in mouse models of acute and chronic hemolysis. We demonstrated that hemolysis was associated with a significant depletion of intracellular iron levels and increased expression of the sole iron exporter protein, ferroportin. The pathophysiological relevance of this mechanism was further demonstrated in sickle cell anemia mice, which, despite chronic hemolysis, maintained high ferroportin expression and increased iron export. We identified a redox active iron species and superoxide as regulators for ferroportin induction by heme. Scavenging the ROS production, by use of a pharmacological antioxidant N-acetylcysteine, prevented ferroportin induction and normalized intracellular iron levels in macrophages and in experimentally induced hemolysis in mice. Innovation: Our data propose that scavenging ROS levels may be a novel therapeutic strategy to balance intracellular iron levels and systemic iron influx in conditions associated with heme overload. Conclusion: This study identifies that the pro-oxidant, and not the proinflammatory, actions of heme profoundly impact on iron homeostasis by critically regulating the expression of ferroportin and iron export in hemolytic conditions. Antioxid. Redox Signal. 29, 484–499. Mary Ann Liebert, Inc. 2018-08-10 2018-08-10 /pmc/articles/PMC6034398/ /pubmed/29212341 http://dx.doi.org/10.1089/ars.2017.7089 Text en © Naveen Kumar Tangugu et al., 2018; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attributions License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Communications Tangudu, Naveen Kumar Alan, Betül Vinchi, Francesca Wörle, Katharina Lai, Dilay Vettorazzi, Sabine Leopold, Kerstin Vujić Spasić, Maja Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model |
title | Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model |
title_full | Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model |
title_fullStr | Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model |
title_full_unstemmed | Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model |
title_short | Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model |
title_sort | scavenging reactive oxygen species production normalizes ferroportin expression and ameliorates cellular and systemic iron disbalances in hemolytic mouse model |
topic | Original Research Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034398/ https://www.ncbi.nlm.nih.gov/pubmed/29212341 http://dx.doi.org/10.1089/ars.2017.7089 |
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