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Extracellular histones are a target in myocardial ischaemia–reperfusion injury
AIMS : Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. The objective of this study was to establish whether extracellular histone release contribut...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930072/ https://www.ncbi.nlm.nih.gov/pubmed/33878183 http://dx.doi.org/10.1093/cvr/cvab139 |
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author | Shah, Mohammed He, Zhenhe Rauf, Ali Beikoghli Kalkhoran, Siavash Heiestad, Christina Mathisen Stensløkken, Kåre-Olav Parish, Christopher R Soehnlein, Oliver Arjun, Sapna Davidson, Sean M Yellon, Derek |
author_facet | Shah, Mohammed He, Zhenhe Rauf, Ali Beikoghli Kalkhoran, Siavash Heiestad, Christina Mathisen Stensløkken, Kåre-Olav Parish, Christopher R Soehnlein, Oliver Arjun, Sapna Davidson, Sean M Yellon, Derek |
author_sort | Shah, Mohammed |
collection | PubMed |
description | AIMS : Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. METHODS AND RESULTS : Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone-H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralizing compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size. CONCLUSION : Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. |
format | Online Article Text |
id | pubmed-8930072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-89300722022-03-18 Extracellular histones are a target in myocardial ischaemia–reperfusion injury Shah, Mohammed He, Zhenhe Rauf, Ali Beikoghli Kalkhoran, Siavash Heiestad, Christina Mathisen Stensløkken, Kåre-Olav Parish, Christopher R Soehnlein, Oliver Arjun, Sapna Davidson, Sean M Yellon, Derek Cardiovasc Res Original Articles AIMS : Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. METHODS AND RESULTS : Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone-H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralizing compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size. CONCLUSION : Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. Oxford University Press 2021-04-20 /pmc/articles/PMC8930072/ /pubmed/33878183 http://dx.doi.org/10.1093/cvr/cvab139 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Shah, Mohammed He, Zhenhe Rauf, Ali Beikoghli Kalkhoran, Siavash Heiestad, Christina Mathisen Stensløkken, Kåre-Olav Parish, Christopher R Soehnlein, Oliver Arjun, Sapna Davidson, Sean M Yellon, Derek Extracellular histones are a target in myocardial ischaemia–reperfusion injury |
title | Extracellular histones are a target in myocardial ischaemia–reperfusion injury |
title_full | Extracellular histones are a target in myocardial ischaemia–reperfusion injury |
title_fullStr | Extracellular histones are a target in myocardial ischaemia–reperfusion injury |
title_full_unstemmed | Extracellular histones are a target in myocardial ischaemia–reperfusion injury |
title_short | Extracellular histones are a target in myocardial ischaemia–reperfusion injury |
title_sort | extracellular histones are a target in myocardial ischaemia–reperfusion injury |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930072/ https://www.ncbi.nlm.nih.gov/pubmed/33878183 http://dx.doi.org/10.1093/cvr/cvab139 |
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