Circulation Research. 2002
Published online before print November 21, 2002, doi: 10.1161/01.RES.0000048195.15637.AC
Published online before print November 21, 2002, doi: 10.1161/01.RES.0000048195.15637.AC
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Submitted on June 28, 2002
Revised on November 8, 2002
Accepted on November 8, 2002
Oxidative Stress-Induced Iron Signaling Is Responsible for Peroxide-Dependent Oxidation of Dichlorodihydrofluorescein in Endothelial Cells. Role of Transferrin Receptor-Dependent Iron Uptake in Apoptosis
Yoshiko Tampo ;
From the Biophysics Research Institute and Free Radical Research Center (Y.T., S.K., S.V.K., A.K., J.J., B.K.) and Division of Neoplastic Diseases (C.R.C.), Medical College of Wisconsin, Milwaukee, Wis.
* To whom correspondence should be addressed. E-mail: balarama{at}mcw.edu.
Dichlorodihydrofluorescein (DCFH) is one of the most frequently used probes for detecting intracellular oxidative stress. In this study, we report that H2O2-dependent intracellular oxidation of DCFH to a green fluorescent product, 2',7'-dichlorofluorescein (DCF), required the uptake of extracellular iron transported through a transferrin receptor (TfR) in endothelial cells. H2O2-induced DCF fluorescence was inhibited by the monoclonal IgA-class anti-TfR antibody (42/6) that blocked TfR endocytosis and the iron uptake. H2O2-mediated inactivation of cytosolic aconitase was responsible for activation of iron regulatory protein-1 and increased expression of TfR, resulting in an increased iron uptake into endothelial cells. H2O2-mediated caspase-3 proteolytic activation was inhibited by anti-TfR antibody. Similar results were obtained in the presence of a lipid hydroperoxide. We conclude that hydroperoxide-induced DCFH oxidation and endothelial cell apoptosis required the uptake of extracellular iron by the TfR-dependent iron transport mechanism and that the peroxide-induced iron signaling, in general, has broader implications in oxidative vascular biology.
Key words: transferrin receptor • dichlorodihydrofluorescein • caspase activation • apoptosis • oxidative stress
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