Crosstalk of Hypoxia-Mediated Signaling Pathways in Upregulating Plasminogen Activator Inhibitor-1 Expression in Keloid Fibroblasts

Qunzhou Zhang, Yidi Wu, Cindy H. Chau, David K. Ann, Charles N. Bertolami, Anh D. Le

Research output: Contribution to journalArticlepeer-review


Keloids are skin fibrotic conditions characterized by an excess accumulation of extracellular matrix (ECM) components secondary to trauma or surgical injuries. Previous studies have shown that plasminogen activator inhibitor-1 (PAI-1) can be upregulated by hypoxia and may contribute to keloid pathogenesis. In this study we investigate the signaling mechanisms involved in hypoxia-mediated PAI-1 expression in keloid fibroblasts. Using Northern and Western blot analysis, transient transfections, and pharmacological agents, we demonstrate that hypoxia-induced upregulation of PAI-1 expression is mainly controlled by hypoxia inducible factors-1α (HIF-1α) and that hypoxia leads to a rapid and transient activation of phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2). Treatment of cells with PI-3K/Akt inhibitor (LY294002) and tyrosine protein kinase inhibitor (genistein) significantly attenuated hypoxia-induced PAI-1 mRNA and protein expression as well as promoter activation, apparently via an inhibition of the hypoxia-induced stabilization of HIF-1α protein, attenuation of the steady-state level of HIF-1α mRNA, and its DNA-binding activity. Even though disruption of ERK1/2 signaling pathway by PD98059 abolished hypoxia-induced PAI-1 promoter activation and mRNA/protein expression in keloid fibroblasts, it did not inhibit the hypoxia-mediated stabilization of HIF-1α protein and the steady-state level of HIF-1α mRNA nor its DNA binding activity. Our findings suggest that a combination of several signaling pathways, including ERK1/2, PI3-K/Akt, and protein tyrosine kinases (PTKs), may contribute to the hypoxia-mediated induction of PAI-1 expression via activation of HIF-1α in keloid fibroblasts.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalJournal of Cellular Physiology
Issue number1
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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