Extracellular histones are a target in myocardial ischaemia–reperfusion injury

Abstract 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 c...

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Published inCardiovascular research Vol. 118; no. 4; pp. 1115 - 1125
Main Authors 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
Format Journal Article
LanguageEnglish
Published England Oxford University Press 16.03.2022
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Summary:Abstract 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. Graphical Abstract
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ISSN:0008-6363
1755-3245
1755-3245
DOI:10.1093/cvr/cvab139