title: Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages.
abstract: OBJECTIVE
  Sodium 9-acetoxyltanshinone IIA sulfonate (ZY-1A4), a novel compound derived from sodium 9-hydroxyltanshinone IIA sulfonate, was synthesized with potential biological activities. This study aimed to explore the effects of ZY-1A4 on lipopolysaccharide (LPS)-triggered inflammatory response and the underlying mechanisms.
  
  
  METHODS
  Activation of RAW264.7 macrophages was induced by LPS. The effects of ZY-1A4 on inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) generation, nuclear factor-κB (NF-κB) activation, heme oxygenase-1 (HO-1) expression, and nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway were evaluated to elucidate its underlying mechanisms on inflammatory responses.
  
  
  RESULTS
  ZY-1A4 concentration-dependently reduced iNOS expression and NO production, and inhibited c-Jun-N-terminal kinase 1/2 (JNK1/2) phosphorylation and NF-κB activation in LPS-stimulated macrophages. In addition, ZY-1A4 concentration- and time-dependently induced HO-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of Nrf2, while the effect of ZY-1A4 was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Intriguingly, pharmacological inactivation of HO-1 with zinc protoporphyrin IX reversed anti-inflammatory effect of ZY- 1A4, but the anti-inflammatory effect of ZY-1A4 was largely mimicked by HO-1 by-products carbon monoxide and bilirubin. Furthermore, the inhibitory effect of ZY-1A4 on LPS-induced iNOS expression and NO release was abolished by HO-1 siRNA or LY294002.
  
  
  CONCLUSIONS
  Our results demonstrated that ZY-1A4 suppressed LPS-induced iNOS expression and NO generation via modulation of NF-κB activation and HO-1 expression. This new finding might shed light to the prevention and therapy of cardiovascular diseases.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Liu
authors.forename: Xi-Ling
authors.initials: XL
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xin
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.forename: Qiu-Yan
authors.initials: QY
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yi-Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D027561:Salvia miltiorrhiza / Q000737:chemistry; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010616:Phenanthrenes; D009569:Nitric Oxide; C024894:tanshinone II A sodium sulfonate; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1