title: 17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats.
abstract: Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG), a heat shock protein (HSP) 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS) induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p.) was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h) induced endotoxemia. The elevated levels of alanine aminotransferase (ALT), creatine phosphokinase (CPK), lactate dehydrogenase, creatinine, nitric oxide (NO) metabolites, IL-6, and TNF-α in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and heme oxygenase (HO)-1, and suppressed inducible nitric oxide synthase (iNOS) and phosphorylated NF-κB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p.), as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Li
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Hsin-Hsueh
authors.initials: HH
authors.lastname: Shen
authors.affiliation: Department of Physiology & Biophysics, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Pao-Yun
authors.initials: PY
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Chu
authors.affiliation: Division of Cardiology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Hwong-Ru
authors.initials: HR
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, Taipei Medical University, Taipei, Taiwan.|Department of Anesthesiology, Catholic Mercy Hospital, Hsinchu, Taiwan.
authors.forename: Kwok-Keung
authors.initials: KK
authors.lastname: Lam
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yen-Mei
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D003404:Creatinine / Q000097:blood; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D009569:Nitric Oxide; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D003402:Creatine Kinase; C505410:Casp3 protein, rat; D053148:Caspase 3