Mechanisms of cardiomyocyte dysfunction induced by extracellular histones
- 1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds
Abstract
Circulating histones released from damaged cells cause secondary impairment to organs, including the heart. Here, we investigate their effects and the underlying pathological mechanisms on isolated ventricular cardiomyocytes. Exogenous H3 or H4 (0.01–1 µg ml−1) induced progressive membrane depolarization, action potential prolongation, membrane potential oscillations resembling early afterdepolarizations, and Ca2+ dysregulation. These changes resulted from a histone-induced nonspecific depolarizing current with a linear current voltage relationship, consistent with the formation of transient pores in the sarcolemma. These effects were replicated by the addition of endogenous H3 isolated from media surrounding myocytes where necrosis has been induced. Acetylation by histone deacetylase inhibitors improved cell viability, reduced and delayed the electrophysiological changes observed with nonacetylated H3. Recombinant pan-acetyl H3 eliminated lethal depolarization. Complexes of histone and histone antibodies produced smaller depolarizations after longer exposures and delayed electrophysiological response. This is consistent with neutralization of the positive charges associated with the histone and suggest a novel therapeutic strategy to limit pathology resulting from histone toxicity.
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BibTeX
@article{alowais2026mechanisms,
title = {{Mechanisms of cardiomyocyte dysfunction induced by extracellular histones}},
author = {Moza M. Al-Owais and Zhaokang Yang and Derek S. Steele and Arun V. Holden},
journal = {Cell Death Discovery},
year = {2026},
month = jul,
doi = {10.1038/s41420-026-03274-w},
url = {https://doi.org/10.1038/s41420-026-03274-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mechanisms of cardiomyocyte dysfunction induced by extracellular histones
AU - Moza M. Al-Owais
AU - Zhaokang Yang
AU - Derek S. Steele
AU - Arun V. Holden
PY - 2026
DA - 2026/07/01
JO - Cell Death Discovery
DO - 10.1038/s41420-026-03274-w
UR - https://doi.org/10.1038/s41420-026-03274-w
AB - Circulating histones released from damaged cells cause secondary impairment to organs, including the heart. Here, we investigate their effects and the underlying pathological mechanisms on isolated ventricular cardiomyocytes. Exogenous H3 or H4 (0.01–1 µg ml−1) induced progressive membrane depolarization, action potential prolongation, membrane potential oscillations resembling early afterdepolarizations, and Ca2+ dysregulation. These changes resulted from a histone-induced nonspecific depolarizing current with a linear current voltage relationship, consistent with the formation of transient pores in the sarcolemma. These effects were replicated by the addition of endogenous H3 isolated from media surrounding myocytes where necrosis has been induced. Acetylation by histone deacetylase inhibitors improved cell viability, reduced and delayed the electrophysiological changes observed with nonacetylated H3. Recombinant pan-acetyl H3 eliminated lethal depolarization. Complexes of histone and histone antibodies produced smaller depolarizations after longer exposures and delayed electrophysiological response. This is consistent with neutralization of the positive charges associated with the histone and suggest a novel therapeutic strategy to limit pathology resulting from histone toxicity.
SN - 2058-7716
ER -