Circulation Research. 2003;92:56-63
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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© 2003 American Heart Association, Inc.
Cellular Biology |
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
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.
Correspondence to B. Kalyanaraman, PhD, Biophysics Research Institute, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. 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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