Published online before print October 13, 2005, doi: 10.1161/01.ATV.0000190610.63878.20
© 2005 American Heart Association, Inc.
Vascular Biology |
Tumor Necrosis Factor-
–Induced Iron Sequestration and Oxidative Stress in Human Endothelial Cells
From the Department of Internal Medicine, Division of Kidney and Dialysis (M.N., Y.O., K.I., R.M., K.M., Y.K., M.I., T.N.) and the Department of Biochemistry (T.O., H.E., K.S.), Hyogo College of Medicine, Hyogo, Japan.
Correspondence to Masayoshi Nanami, Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, 1-1 Mukogawa-cho, Hyogo 663-8501, Japan. E-mail m-nanami{at}hyo-med.ac.jp
Objective— Tumor necrosis factor (TNF)-
–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- 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- 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- accelerated hydroxyl radical production.
Conclusions— TNF- could cause intracellular iron sequestration, which may participate importantly in the pathophysiology of atherosclerosis and cardiovascular disease.
TNF- induced upregulation of iron import proteins and downregulation of iron export protein in human endothelial cells via a posttranscriptional mechanism. These modifications could cause accumulation of iron in endothelium, increasing oxidative stress that might contribute importantly to the pathophysiologic processes of atherosclerosis.
Key Words: cytokines • endothelium • free radicals • inflammation • iron
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