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Copper and myeloperoxidase-modified LDLs activate Nrf2 through different pathways of ROS production in macrophages.
MedLine Citation:
PMID:  20446765     Owner:  NLM     Status:  In-Process    
Low-density lipoprotein (LDL) oxidation is a key step in atherogenesis, promoting the formation of lipid-laden macrophages. Here, we compared the effects of copper-oxidized LDLs (OxLDLs) and of the more physiologically relevant myeloperoxidase-oxidized LDLs (MoxLDLs) in murine RAW264.7 macrophages and in human peripheral blood monocyte-derived macrophages. Both oxidized LDLs, contrary to native LDLs, induced foam cell formation and an intracellular accumulation of reactive oxygen species (ROS). This oxidative stress was responsible for the activation of the NF-E2-related factor 2 (Nrf2) transcription factor, and the subsequent Nrf2-dependent overexpression of the antioxidant genes, Gclm and HO-1, as evidenced by the invalidation of Nrf2 by RNAi. MoxLDLs always induced a stronger response than OxLDLs. These differences could be partly explained by specific ROS-producing mechanisms differing between OxLDLs and MoxLDLs. Whereas both types of oxidized LDLs caused ROS production partly by NADPH oxidase, only MoxLDLs-induced ROS production was dependent on cytosolic PLA2. This study highlights that OxLDLs and MoxLDLs induce an oxidative stress, through distinct ROS-producing mechanisms, which is responsible for the differential activation of the Nrf2 pathway. These data clearly suggest that results obtained until now with copper oxidized-LDLs should be carefully reevaluated, taking into consideration physiologically more relevant oxidized LDLs.
Damien Calay; Alexandre Rousseau; Laurine Mattart; Vincent Nuyens; Cédric Delporte; Pierre Van Antwerpen; Nicole Moguilevsky; Thierry Arnould; Karim Zouaoui Boudjeltia; Martine Raes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  13     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-07     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1491-502     Citation Subset:  IM    
Laboratory of Biochemistry and Cellular Biology, University of Namur (FUNDP)—URBC, Namur, Belgium.
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