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Volume 271, Number 25, Issue of June 21, 1996 pp. 14773-14778
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Ceruloplasmin Enhances Smooth Muscle Cell- and Endothelial Cell-mediated Low Density Lipoprotein Oxidation by a Superoxide-dependent Mechanism

(Received for publication, October 17, 1995, and in revised form, January 31, 1996)

From the Department of Cell Biology, Cleveland Clinic Research Institute, Cleveland, Ohio 44195

Cultured vascular smooth muscle cells (SMC) and endothelial cells (EC) stimulate low density lipoprotein (LDL) oxidation by free radical-mediated, transition metal-dependent mechanisms. The physiological source(s) of metal ions is not known; however, purified ceruloplasmin, a plasma protein containing 7 coppers, oxidizes LDL in vitro. We now show that ceruloplasmin also increases LDL oxidation by vascular cells. In metal ion-free medium, human ceruloplasmin increased bovine aortic SMC- and EC-mediated LDL oxidation by up to 30- and 15-fold, respectively. The maximal response was at 100-300 µg ceruloplasmin/ml, a level at or below the unevoked physiological plasma concentration. Oxidant activity was dependent on protein structure as a specific proteolytic cleavage or removal of one of the seven ceruloplasmin copper atoms inhibited activity. Three lines of evidence indicated a critical role for cellular superoxide (O₂) in ceruloplasmin-stimulated oxidation. First, the rate of production of O₂ by cells correlated with their rates of LDL oxidation. Second, superoxide dismutase effectively blocked ceruloplasmin-stimulated oxidation by both cell types. Finally, O₂ production by SMC quantitatively accounted for the observed rate of LDL oxidation. To show this, the course of O₂ production by SMC was simulated by repeated addition of xanthine and xanthine oxidase to culture medium under cell-free conditions. Neither ceruloplasmin nor O₂ alone increased LDL oxidation, but together they completely reconstituted the oxidation rate of ceruloplasmin-stimulated SMC. These results are the first to show that ceruloplasmin stimulates EC- and SMC-mediated oxidation of LDL and that cell-derived O₂ accounts quantitatively for metal-dependent, free radical-initiated oxidation of LDL by these cells.

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