Nickel requires hypoxia-inducible factor-1 alpha, not redox signaling, to induce plasminogen activator inhibitor-1

Human epidemiological and animal studies have associated inhalation of nick el dusts with an increased incidence of pulmonary fibrosis. At the cellular level, particulate nickel subsulfide inhibits fibrinolysis by transcriptio nally inducing expression of plasminogen activator inhibitor (PAI)-1, an in hibitor of the urokinase-type plasminogen activator. Because nickel is know n to mimic hypoxia, the present study examined whether nickel transcription ally activates PAI-1 through the hypoxia-inducible factor (HIF)-1 alpha sig naling pathway. The involvement of the NADPH oxidase complex, reactive oxyg en species, and kinases in mediating nickel-induced HIF-1 alpha signaling w as also investigated. Addition of nickel to BEAS-2B human airway epithelial cells increased HIF-1 alpha protein levels and elevated PAI-1 mRNA levels. Pretreatment of cells with the extracellular signal-regulated kinase inhib itor U-0126 partially blocked HIF-1 alpha protein and PAI-1 mRNA levels ind uced by nickel, whereas antioxidants and NADPH oxidase inhibitors had no ef fect. Pretreating cells with antisense, but not sense, oligonucleotides to HIF-1 alpha mRNA abolished nickel-stimulated increases in PAI-1 mRNA. These data indicate that signaling through extracellular signal-regulated kinase and HIF-1 alpha is required for nickel-induced transcriptional activation of PAI-1.