Extracellular
histones induce lethal
thrombosis by promoting platelet aggregation, neutrophil migration, and cell
injuries.
Heparin, which has negative charges, can bind to extracellular
histones; however,
heparin strongly inhibits the activation of coagulation. Since
chondroitin sulfate (CS) shows less effect on the coagulation system than
heparin does, CS has the potential to become an effective
drug for lethal
thrombosis with high risk of
bleeding. To elucidate the therapeutic mechanisms of CS in lethal
thrombosis, we investigated the interaction between CS and extracellular
histones. Mouse vascular endothelial cells were incubated with
histones in the presence of
heparin or CS, and the expression of
caspase-3/7 was measured. The interactions between
histones and
heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by
histones was inhibited by treatment with
heparin or CS.
Heparin and CS showed strong binding to
histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with
heparin or CS. Moreover, CS showed less effect on the coagulation system than
heparin did. These results suggested that CS can be a novel agent for lethal
thrombosis with the risk for
hemorrhage. Since vascular endothelial cell
injuries occur at an early stage of lethal
thrombosis, administration of CS might be a useful approach.