Myocardial dysfunction is a major consequence of
septic shock and contributes to the high mortality of
sepsis. High-mobility group box 1 (
HMGB1) serves as a late mediator of lethality in
sepsis. We have reported that
glucan phosphate (GP) attenuates cardiac dysfunction and increases survival in cecal
ligation and
puncture (CLP)-induced septic mice. In the present study, we examined the effect of GP on
HMGB1 translocation from the nucleus to the cytoplasm in the myocardium of septic mice. GP was administered to mice 1 h before induction of CLP.
Sham-operated mice served as control. The levels of
HMGB1,
Toll-like receptor 4 (TLR4), and NF-κB binding activity were examined. In an in vitro study, H9C2 cardiomyoblasts were treated with
lipopolysaccharide (LPS) in the presence or absence of GP. H9C2 cells were also transfected with Ad5-IκBα mutant, a super repressor of NF-κB activity, before LPS stimulation. CLP significantly increased the levels of
HMGB1, TLR4, and NF-κB binding activity in the myocardium. In contrast, GP administration attenuated CLP-induced
HMGB1 translocation from the nucleus to the cytoplasm and reduced CLP-induced increases in TLR4 and NF-κB activity in the myocardium. In vitro studies showed that GP prevented LPS-induced
HMGB1 translocation and NF-κB binding activity. Blocking NF-κB binding activity by Ad5-IκBα attenuated LPS-induced
HMGB1 translocation. GP administration also reduced the LPS-stimulated interaction of
HMGB1 with TLR4. These data suggest that attenuation of
HMGB1 translocation by GP is mediated through inhibition of NF-κB activation in CLP-induced
sepsis and that activation of NF-κB is required for
HMGB1 translocation.