Key result
Extracellular histones induce cardiomyocyte electrophysiological dysfunction, mitigated by neutralization or acetylation.
Why the study?
Circulating histones released from damaged cells cause secondary organ impairment, including the heart, but their effects and underlying pathological mechanisms on ventricular cardiomyocytes required investigation.
Extracellular histones induce cardiomyocyte dysfunction through non-selective sarcolemmal leak and Ca2+ dysregulation, which can be mitigated by histone acetylation or neutralizing antibodies, suggesting a potential therapeutic strategy for histone toxicity.
Does not support clinical translation; hypothesis-generating for histone-targeted therapies in cardiac injury.
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 Ca 2+ 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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Al‐Owais et al. (2026) studied Cardiomyocyte dysfunction. Extracellular histones (H3 or H4) vs. Control conditions was evaluated on Membrane depolarization and action potential prolongation. Exogenous histones H3 and H4 induced progressive membrane depolarization, action potential prolongation, and Ca2+ dysregulation in isolated cardiomyocytes, effects that were reduced by histone acetylation or neutralizing antibodies.
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