Chromium silences nickel‐induced vascular endothelial growth factor (VEGF) expression in human airway epithelial cells

Abstract

Co‐exposure to chromium(VI) (Cr(VI)) and nickel (Ni) is a widely recognized pulmonary health hazard. Chronic inhalation of either metal promotes lung disease and co‐exposures to metal mixtures may pose even greater risks. VEGF is essential in lung injury and repair since loss of VEGF expression causes apoptosis and emphysema. The current study investigates the hypothesis that Cr(VI) may contribute to airway injury by silencing Ni‐induced VEGF expression in human bronchial airway (BEAS‐2B) epithelial cells. VEGF mRNA levels were measured in cells left untreated or exposed to a non‐cytotoxic concentration of Cr(VI) (5μM) prior to the addition of 200μM Ni. Exposure to Cr(VI) alone had no effect on basal VEGF expression, but inhibited Ni‐induced VEGF mRNA transcripts. Ni induction of VEGF requires HIF‐1α transactivation. Pretreatment with Cr(VI) blocked Ni stabilization of HIF‐1□ protein levels and stimulation of a hypoxia response element (HRE)‐driven luciferase reporter. These data suggest that Cr(VI) inhibits Ni‐induced VEGF mRNA expression by disrupting signaling events mediating Ni stimulation of the HIF‐1α pathway. This study provides mechanistic insight into potential epigenetic interactions of metal mixtures and support future investigation of the role of these interactions in the severity of pulmonary injury and the etiology of lung diseases. Supported by ES10638.