Background/purpose: 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).
Conclusion: 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.
Keywords: cyclosporine A; gingival fibroblasts; gingival overgrowth; hypoxia-inducible factor-1α; plasminogen activator inhibitor-1.
Copyright © 2012. Published by Elsevier B.V.