title: Involvement of HSP70 and HO-1 in the protective effects of raloxifene on multiple organ dysfunction syndrome by endotoxemia in ovariectomized rats.
abstract: OBJECTIVE
  Accumulating evidence demonstrates that raloxifene, a selective estrogen receptor modulator, possesses anti-inflammatory action. This study evaluates the preventive effects of long-term treatment of raloxifene on acute inflammation and multiple organ dysfunction syndrome (MODS) in ovariectomized (OVX) rats with endotoxemia and its underlying mechanism of action.
  
  
  METHODS
  Adult female rats were OVX bilaterally to induce estrogen insufficiency. OVX rats were administered with raloxifene (1 mg/kg, gavage, once daily) for 8 weeks, beginning 1 week after surgery, followed by induction of sepsis via intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg) for 4 hours. LPS-activated RAW 264.7 cells were used to investigate the mechanism of raloxifene.
  
  
  RESULTS
  Ovariectomy amplified the endotoxemia-induced hypotensive effect, MODS, and superoxide anion production in the myocardium. The levels of inducible nitric oxide synthase, high mobility group box 1, and nuclear factor-κB p65 protein increased in OVX rats 6 hours after LPS initiation. Raloxifene mitigated MODS, together with reduced inducible nitric oxide synthase induction and fewer superoxide anions in organs. Raloxifene induced high levels of heat shock protein 70 (HSP70) and heme oxygenase 1 (HO-1), which are associated with an increase in the transcription factor heat shock factor-1 and Nrf-2, respectively. Pretreatment with quercetin, an inhibitor of HSP70, or SnPP, an inhibitor of HO-1, reversed the protective effects of raloxifene in septic OVX rats and LPS-activated macrophages.
  
  
  CONCLUSIONS
  Long-term treatment with raloxifene reduces the severity of sepsis in OVX rats, attributed from up-regulation of HSP70 and HO-1 to exert the antioxidant and anti-inflammatory capacities. These findings provide new insights into bacterial infection during menopause and the molecular mechanism of raloxifene.
authors.affiliation: 1Department and Institute of Pharmacology 2Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 3Department of Pharmacy, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan 4Department of Physiology & Biophysics, National Defense Medical Center, Taipei, Taiwan 5Department of Nursing, Hung Kuang University, Taichung, Taiwan 6Department of Pharmacology, Taipei Medical University, Taipei, Taiwan 7Department of Anesthesiology, Catholic Mercy Hospital, Hsinchu, Taiwan.
authors.forename: Hsin-Hsueh
authors.initials: HH
authors.lastname: Shen
authors.forename: Shieh-Yang
authors.initials: SY
authors.lastname: Huang
authors.forename: Pao-Yun
authors.initials: PY
authors.lastname: Cheng
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Chu
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Chen
authors.forename: Kwok-Keung
authors.initials: KK
authors.lastname: Lam
authors.forename: Yen-Mei
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000378:metabolism; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D051547:Heme Oxygenase-1