Abstract
Divalent metal ions such as nickel, cobalt, and manganese are known to induce hypoxia-inducible factors (HIFs) over several hours and are implicated in inflammatory responses; however, their roles in vascular tissue remain incompletely understood. In addition to long-term effects, metal ions also can elicit rapid cellular responses, such as calcium mobilization and the phosphorylation of signaling molecules, within seconds to minutes. These rapid responses cannot be solely explained by HIF activation. Here, we investigated the contributions of both HIFs and proton-sensing ovarian cancer G protein-coupled receptor 1 (OGR1) to metal ion-induced inflammatory responses in human coronary artery smooth muscle cells. While metal ions induced HIF-α subunits and upregulated vascular endothelial growth factor a and leptin expression through relatively slow pathways, they simultaneously triggered the rapid induction of interleukin-6 and cyclooxygenase-2 via OGR1. Interleukin-6 secretion induced by metal ions and acidic pH was mediated through the OGR1/Gq/11/Ca2+ pathway, including PKC, protein kinase D, and Ca2+/calcium/calmodulin-dependent protein kinase II, with a major contribution from the OGR1/Gq/11/protein kinase D/CREB signaling axis. Furthermore, OGR1 could detect subtle changes in metal ion concentrations under mildly acidic conditions, suggesting a synergistic mechanism. We conclude that metal ions exert dual-phase inflammatory effects in vascular tissue: a rapid response via OGR1 signaling and a slower response via HIF-mediated transcription, both contributing to vascular inflammation.