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J. Biol. Chem., Vol. 281, Issue 38, 27991-28001, September 22, 2006

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Dual Role of Peroxiredoxin I in Macrophage-derived Foam Cells^*

James P. Conway and Michael Kinter¹

From the Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106 and the Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195

We and others have shown that foam cell formation initiated by exposing macrophages to oxidized low density lipoprotein (oxLDL) triggers the differential expression of a number of proteins. Specifically, our experiments have identified peroxiredoxin I (Prx I) as one of these up-regulated proteins. The peroxiredoxins, a family of peroxidases initially described for their antioxidant capability, have generated recent interest for their potential to regulate signaling pathways. Those studies, however, have not examined peroxiredoxin for a potential dual functionality as both cytoprotective antioxidant and signal modulator in a single, oxidant-stressed system. In this report, we examine the up-regulation of Prx I in macrophages in response to oxLDL exposure and its ability to function as both antioxidant enzyme and regulator of p38 MAPK activation. As an antioxidant, induction of Prx I expression led to improved cell survival following treatment with oxLDL or tert-butyl hydroperoxide. The improved survival coincided with a decrease in measurable reactive oxygen species (ROS), and both the increased survival and reduced ROS were reversed by Prx I small interfering RNA transfection. Additionally, our data show that activation of p38 MAPK in oxLDL-treated macrophages was dependent on the up-regulation of Prx I. Reduction of Prx I expression by small interfering RNA transfection resulted in a significant decrease in p38 MAPK activation, whereas the up-regulation of Prx I expression with either oxLDL or ethoxyquin led to increased p38 MAPK activation. These results are consistent with multiple roles for Prx I in macrophage-derived foam cells that include functionality as both an antioxidant and a regulator of oxidant-sensitive signal transduction.

Received for publication, May 25, 2006 , and in revised form, July 13, 2006.

^* This work was supported by the Cleveland Clinic Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell Biology NC10, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-7170; Fax: 216-444-9404; E-mail: kinterm{at}ccf.org.

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