2005/10/14 by Masayoshi Nanami, Tomomi Ookawara, Yoshinaga Otaki +8 · 1 citation
Chemistry · Medicine · #Biochemistry #Biology #Blood properties and coagulation #Cell biology #Chemistry #DMT1 #Downregulation and upregulation #Endocrinology #Endothelial activation #Endothelium #Erythropoietin and Anemia Treatment #Ferroportin #Hepcidin #Immunology #In vitro #Inflammation #Intracellular #Iron Metabolism and Disorders #Oxidative stress #Reactive oxygen species #Transferrin #Transferrin receptor #Transporter #Tumor necrosis factor alpha #Umbilical vein
paper · pdf · doi:10.1161/01.atv.0000190610.63878.20
openalex publication_date 2005/10/14 · openalex created_date 2016/06/24 · openalex updated_date 2026/06/26
OBJECTIVE: Tumor necrosis factor (TNF)-alpha-induced endothelial injury, which is associated with atherosclerosis, is mediated by intracellular reactive oxygen species. Iron is essential for the amplification of oxidative stress. We tested whether TNF-alpha accelerated iron accumulation in vascular endothelium, favoring synthesis of hydroxyl radical. METHODS AND RESULTS: Diverse iron transporters, including iron import proteins (transferrin receptor [TfR] and divalent metal transporter 1 [DMT1]) and an iron export protein (ferroportin 1 [FP1]) coexist in human umbilical endothelial cells (HUVECs). TNF-alpha caused upregulation of TfR and DMT1 and downregulation of FP1, which were demonstrated in mRNA as well as protein levels. These changes in iron transporters were accompanied by accumulation of iron that was both transferrin-dependent and transferrin-independent. Modifications of these mRNAs were regulated post-transcriptionally, and were coordinated with activation of binding activity of iron regulatory protein 1 to the iron responsive element on transporter mRNAs. Using a salicylate trap method, we observed that only simultaneous exposure of endothelial cells to iron and TNF-alpha accelerated hydroxyl radical production. CONCLUSIONS: TNF-alpha could cause intracellular iron sequestration, which may participate importantly in the pathophysiology of atherosclerosis and cardiovascular disease.