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Glucan phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-κB activation
Tuanzhu Ha1, Yeling Xia, Xiang Liu
1Department of Surgery, East Tennessee State University, Johnson City, Tennessee 37614-0575, USA.
Insights
Glucan phosphate (GP) reduces cardiac dysfunction in sepsis by preventing the translocation of High-mobility group box 1 (HMGB1) from the nucleus to the cytoplasm. This mechanism involves inhibiting NF-κB activation, crucial for HMGB1 movement in sepsis.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Sepsis-induced myocardial dysfunction significantly increases mortality.
- High-mobility group box 1 (HMGB1) is a key mediator in sepsis lethality.
- Glucan phosphate (GP) has shown potential in improving survival and attenuating cardiac dysfunction in sepsis models.
Purpose of the Study:
- To investigate the effect of GP on HMGB1 translocation in the myocardium during sepsis.
- To elucidate the role of NF-κB activation and Toll-like receptor 4 (TLR4) in GP-mediated cardioprotection.
Main Methods:
- Animal model: Cecal ligation and puncture (CLP) to induce sepsis in mice.
- In vitro model: H9C2 cardiomyoblasts treated with lipopolysaccharide (LPS).
- Assays: Western blotting for HMGB1, TLR4; electrophoretic mobility shift assay (EMSA) for NF-κB binding activity; immunoprecipitation for HMGB1-TLR4 interaction.
Main Results:
- CLP significantly increased myocardial HMGB1, TLR4, and NF-κB activity.
- GP administration attenuated CLP-induced HMGB1 translocation and reduced TLR4 and NF-κB activity.
- In vitro, GP inhibited LPS-induced HMGB1 translocation and NF-κB activation, an effect dependent on NF-κB.
- GP reduced the interaction between HMGB1 and TLR4 stimulated by LPS.
Conclusions:
- GP attenuates HMGB1 translocation in sepsis-induced myocardial dysfunction by inhibiting NF-κB activation.
- NF-κB activation is essential for HMGB1 translocation in this sepsis model.
- GP demonstrates a protective effect against sepsis-induced cardiac dysfunction through modulation of the HMGB1/TLR4/NF-κB pathway.
Abstract:
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.
