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The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease
In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152901/ https://www.ncbi.nlm.nih.gov/pubmed/37144034 http://dx.doi.org/10.3389/fmed.2023.1101501 |
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author | Belcher, John D. Nataraja, Selvaraj Abdulla, Fuad Zhang, Ping Chen, Chunsheng Nguyen, Julia Ruan, Conglin Singh, Maneet Demes, Shilpa Olson, Lyndsay Stickens, Domi Stanwix, Jeff Clarke, Emer Huang, Yongzhao Biddle, Margaret Vercellotti, Gregory M. |
author_facet | Belcher, John D. Nataraja, Selvaraj Abdulla, Fuad Zhang, Ping Chen, Chunsheng Nguyen, Julia Ruan, Conglin Singh, Maneet Demes, Shilpa Olson, Lyndsay Stickens, Domi Stanwix, Jeff Clarke, Emer Huang, Yongzhao Biddle, Margaret Vercellotti, Gregory M. |
author_sort | Belcher, John D. |
collection | PubMed |
description | In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD. |
format | Online Article Text |
id | pubmed-10152901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101529012023-05-03 The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease Belcher, John D. Nataraja, Selvaraj Abdulla, Fuad Zhang, Ping Chen, Chunsheng Nguyen, Julia Ruan, Conglin Singh, Maneet Demes, Shilpa Olson, Lyndsay Stickens, Domi Stanwix, Jeff Clarke, Emer Huang, Yongzhao Biddle, Margaret Vercellotti, Gregory M. Front Med (Lausanne) Medicine In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD. Frontiers Media S.A. 2023-04-18 /pmc/articles/PMC10152901/ /pubmed/37144034 http://dx.doi.org/10.3389/fmed.2023.1101501 Text en Copyright © 2023 Belcher, Nataraja, Abdulla, Zhang, Chen, Nguyen, Ruan, Singh, Demes, Olson, Stickens, Stanwix, Clark, Huang, Biddle and Vercellotti. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Belcher, John D. Nataraja, Selvaraj Abdulla, Fuad Zhang, Ping Chen, Chunsheng Nguyen, Julia Ruan, Conglin Singh, Maneet Demes, Shilpa Olson, Lyndsay Stickens, Domi Stanwix, Jeff Clarke, Emer Huang, Yongzhao Biddle, Margaret Vercellotti, Gregory M. The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease |
title | The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease |
title_full | The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease |
title_fullStr | The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease |
title_full_unstemmed | The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease |
title_short | The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease |
title_sort | bach1 inhibitor asp8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152901/ https://www.ncbi.nlm.nih.gov/pubmed/37144034 http://dx.doi.org/10.3389/fmed.2023.1101501 |
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