title: Glucan phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-κB activation.
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.
authors.affiliation: Department of Surgery, East Tennessee State University, Johnson City, Tennessee 37614-0575, USA.
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Yeling
authors.initials: Y
authors.lastname: Xia
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Jim
authors.initials: J
authors.lastname: Kelley
authors.forename: John
authors.initials: J
authors.lastname: Kalbfleisch
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002432:Cecum / Q000382:microbiology / Q000601:surgery; D002460:Cell Line; D004195:Disease Models, Animal; D005936:Glucans / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D011677:Punctures; D051381:Rats; D018805:Sepsis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D012720:Severity of Illness Index; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D014162:Transfection
chemical_list: D005936:Glucans; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C480175:glucan phosphate; C482199:lipopolysaccharide, E coli O55-B5; D000072000:NF-KappaB Inhibitor alpha