Dual role of peroxiredoxin I in macrophage-derived foam cells.
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.
Conway
James P
JP
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Kinter
Michael
M
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D005487:Foam Cells / Q000187:drug effects / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000633:toxicity; D051379:Mice; D010544:Peroxidases / Q000502:physiology*; D054464:Peroxiredoxins; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000633:toxicity
D006360:Heat-Shock Proteins; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D020122:tert-Butylhydroperoxide; D010544:Peroxidases; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases