Koichi Sato1,2,*, Chihiro Mogi3, Haruka Aoki-Saito4, Tamotsu Ishizuka5, Jun Shirakawa2, T Hideaki Tomura6, Dong-Soon Im7 (1. Laboratory of Signal Transduction Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Japan; 2. Laboratory of Diabetes and Metabolic Disorders, IMCR, Gunma University, Japan; 3. Laboratory of Mucosal Ecosystem Design, IMCR, Gunma University, Japan; 4. Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Japan; 5. Department of Respiratory Medicine, Faculty of Medical Sciences, University of Fukui, Japan; 6 Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Japan. 7. College of Pharmacy, Kyung Hee University, Republic of Korea; *Corresponding Author)
About
Divalent metal ions such as nickel, cobalt and manganese are known to induce hypoxia-inducible factors (HIFs) over several hours and are implicated in the inflammatory responses; however, their roles in vascular tissue remain incompletely understood. In addition to long term effects, metal-ions can also elicit rapid cellular responses, such as calcium mobilization and 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 the proton-sensing ovarian cancer G protein-coupled receptor 1 (OGR1) to metal-ions induced inflammatory responses in human coronary artery smooth muscle cells. While metal-ions induced HIF α-subunits and upregulated VEGFa and leptin expression through relatively slow pathways, they simultaneously triggered rapid induction of IL-6 and COX-2 via OGR1. IL-6 secretion induced by metal ions and acidic pH was mediated through the OGR1/Gq/11/Ca2+ pathway, including PKC, PKD and CaMKII, with a major contribution from the OGR1/Gq/11/PKD2/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.
Paper information
"The proton-sensing OGR1 receptor and hypoxia-inducible factors promote metal ion-induced inflammatory responses in coronary artery smooth muscle cells "
Koichi Sato, Chihiro Mogi, Haruka Aoki-Saito, Tamotsu Ishizuka, Jun Shirakawa, T Hideaki Tomura, Dong-Soon Im.
J Biol Chem 301(12): 110842
PMID: 41135674
doi: 10.1016/j.jbc.2025.110842
Online on Oct 22, 2025
Online URL
https://pubmed.ncbi.nlm.nih.gov/41135674/
