Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to
cancer to
COVID-19. Neutralization of cationic
proteins (such as neutrophil extracellular trap/NET-derived
histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent
defibrotide (a pleiotropic mixture of
oligonucleotides) directly engages
histones and thereby blocks their pathological effects on endothelium. In vitro ,
defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant
histone H4. In vivo ,
defibrotide stabilized the endothelium and protected against
histone-accelerated inferior vena cava
thrombosis in mice. Mechanistically,
defibrotide demonstrated direct and tight binding to
histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from
thromboinflammation with potential implications for myriad NET- and
histone-accelerated disease states.