title: The modulation of hypoxia-inducible factor-1α/plasminogen activator inhibitor-1 axis in human gingival fibroblasts stimulated with cyclosporine A.
abstract: OBJECTIVE
  The prominent side effect of the immunosuppressive drug cyclosporine A (CsA) is gingival overgrowth. Hypoxia-inducible factor (HIF)-1α regulates a wide variety of profibrogenic genes, which are closely associated with tissue fibrosis. The aim of this study was to compare HIF-1α expression in normal gingival tissues and CsA-induced gingival overgrowth specimens and further explore the potential mechanisms that may lead to induction of HIF-1α expression.
  
  
  METHODS
  Fifteen CsA-induced gingival overgrowth specimens and five normal gingival tissues were examined by immunohistochemistry. Western blot was used to investigate the effects of CsA on the expression of HIF-1α in cultured human gingival fibroblasts. The effects of CsA on plasminogen activator inhibitor (PAI)-1 expression were evaluated in environmental hypoxia.
  
  
  RESULTS
  HIF-1α staining in gingival tissue was stronger in CsA-induced gingival overgrowth group than normal gingival group (p < 0.05). The expression of HIF-1α was significantly higher in CsA-induced gingival overgrowth specimens with higher levels of inflammatory infiltrates (p = 0.041). CsA was found to upregulate HIF-1α protein in a dose-dependent manner (p < 0.05). Hypoxia increased CsA-induced PAI-1 protein expression than normoxic conditions (p < 0.05).
  
  
  CONCLUSIONS
  These results suggest that HIF-1α expression is significantly upregulated in CsA-induced gingival overgrowth specimens. The activation of HIF-1α may promote fibrogenesis by an increase of PAI-1 expression and a subsequent elevation of extracellular matrix production in gingival tissues.
authors.affiliation: Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chung-Hung
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Fu-Mei
authors.initials: FM
authors.lastname: Huang
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan; School of Dentistry, Chung Shan Medical University, Taichung, Taiwan. Electronic address: cyc@csmu.edu.tw.
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects*; D005347:Fibroblasts / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D019214:Gingival Overgrowth / Q000139:chemically induced; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D016572:Cyclosporine
keywords: cyclosporine A; gingival fibroblasts; gingival overgrowth; hypoxia-inducible factor-1α; plasminogen activator inhibitor-1