title: Copper and myeloperoxidase-modified LDLs activate Nrf2 through different pathways of ROS production in macrophages.
abstract: 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.
authors.affiliation: Laboratory of Biochemistry and Cellular Biology, University of Namur (FUNDP)—URBC, Namur, Belgium. damien.calay@fundp.ac.be
authors.forename: Damien
authors.initials: D
authors.lastname: Calay
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rousseau
authors.forename: Laurine
authors.initials: L
authors.lastname: Mattart
authors.forename: Vincent
authors.initials: V
authors.lastname: Nuyens
authors.forename: Cédric
authors.initials: C
authors.lastname: Delporte
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
authors.forename: Nicole
authors.initials: N
authors.lastname: Moguilevsky
authors.forename: Thierry
authors.initials: T
authors.lastname: Arnould
authors.forename: Karim Zouaoui
authors.initials: KZ
authors.lastname: Boudjeltia
authors.forename: Martine
authors.initials: M
authors.lastname: Raes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D008077:Lipoproteins, LDL; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D003300:Copper; D009195:Peroxidase