title: The Role of High Mobility Group Box 1 Protein in Interleukin-18-Induced Myofibroblastic Transition of Valvular Interstitial Cells.
abstract: BACKGROUND
  Increased levels of interleukin-18 (IL-18) and high mobility group box 1 protein (HMGB1) have been reported in patients with calcific aortic valve disease (CAVD). However, the role of IL-18 and HMGB1 in the modulation of the valvular interstitial cell (VIC) phenotype remains unclear. We hypothesized that HMGB1 mediates IL-18-induced myofibroblastic transition of VICs.
  
  
  METHODS
  The expression of IL-18, HMGB1 and α-smooth muscle actin (α-SMA) in human aortic valves was evaluated by immunohistochemical staining, real-time polymerase chain reaction and immunoblotting. Plasma concentrations of IL-18 and HMGB1 were measured using the ELISA kit. Cultured human aortic VICs were used as an in vitro model.
  
  
  RESULTS
  Immunohistochemistry and immunoblotting revealed increased levels of IL-18, HMGB1 and α-SMA in calcific valves. Circulating IL-18 and HMGB1 levels were also higher in CAVD patients. In vitro, IL-18 induced upregulation of HMGB1 and α-SMA in VICs. Moreover, IL-18 induced secretion of HMGB1 to the extracellular space and activation of nuclear factor kappa-B (NF-κB). Blockade of NF-κB abrogated the upregulation and release of HMGB1 induced by IL-18. Whereas HMGB1 inhibition attenuated the IL-18-induced expression of α-SMA, HMGB1 enhanced the effect of IL-18.
  
  
  CONCLUSIONS
  We demonstrated for the first time that both tissue and plasma levels of IL-18 and HMGB1 were increased in patients with CAVD. Mechanically, HMGB1 mediated IL-18-induced VIC myofibroblastic transition.
authors.affiliation: Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Guangxia
authors.initials: G
authors.lastname: Wei
authors.forename: Baoqing
authors.initials: B
authors.lastname: Liu
authors.forename: Xianming
authors.initials: X
authors.lastname: Zhou
authors.forename: Hua
authors.initials: H
authors.lastname: Xiao
authors.forename: Nianguo
authors.initials: N
authors.lastname: Dong
authors.forename: Fei
authors.initials: F
authors.lastname: Li
mesh_terms: D001021:Aortic Valve / Q000166:cytology* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D006349:Heart Valve Diseases / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D020382:Interleukin-18 / Q000032:analysis / Q000097:blood / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D024243:HMGB1 Protein; C000589760:IL18 protein, human; D020382:Interleukin-18