title: Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals.
abstract: High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. We tested hypothesis that ascorbic acid (AscA) induces heme oxygenase (HO)-1 which inhibits HMGB1 release in lipopolysaccharide (LPS)-stimulated cells and increases survival of septic mice. AscA increased HO-1 protein expression in a concentration- and time-dependent manner via Nrf2 activation in RAW 264.7 cells. HO-1 induction by AscA was significantly reduced by Nrf2 siRNA-transfected cells. Mutation of cysteine to serine of keap-1 proteins (C151S, C273S, and C288S) lost the ability of HO-1 induction by AscA, due to failure of translocation of Nrf-2 to nucleus. The PI3 kinase inhibitor, LY294002, inhibited HO-1 induction by AscA. Oxyhemoglobin (HbO2), LY294002, and ZnPPIX (HO-1 enzyme inhibitor) reversed effect of AscA on HMGB1 release. Most importantly, administration of AscA (200mg/kg, i.p.) significantly increased survival in LPS-induced endotoxemic mice. In cecal ligation and puncture (CLP)-induced septic mice, AscA reduced hepatic injury and serum HMGB1 and plasminogen activator inhibitor (PAI)-1 in a ZnPPIX-sensitive manner. In addition, AscA failed to increase survival in Nrf2 knockout mice by LPS. Thus, we concluded that high dose of AscA may be useful in the treatment of sepsis, at least, by activation of Nrf2/HO-1 signals.
authors.affiliation: Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: So Ra
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Ha
authors.affiliation: Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Jung Whan
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, University of Ulsan (HTC), Ulsan 680-749, Republic of Korea.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
authors.affiliation: Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea. Electronic address: kcchang@gnu.kr.
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D024243:HMGB1 Protein / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology
chemical_list: D001205:Ascorbic Acid; D002248:Carbon Monoxide; D024243:HMGB1 Protein; D051547:Heme Oxygenase-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D009942:Organometallic Compounds; D019869:Phosphatidylinositol 3-Kinases; C582808:HMGB1 protein, mouse; C495636:Nfe2l2 protein, mouse; C447082:tricarbonyldichlororuthenium (II) dimer; C496542:Hmox1 protein, mouse
keywords: HMGB1; Heme oxygenase; Nrf-2; Phosphatidylinositol-3-kinase; Sepsis