Activation of NADPH oxidase is required for macrophage-mediated oxidation of low-density lipoprotein

Michael Aviram, Mira Rosenblat, Amos Etzioni, Rachel Levy

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


Low-density lipoprotein (LDL) oxidation by arterial wall cells, a key event during early atherogenesis, was suggested to involve the activation of 15-lipoxygenase and/or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We sought to analyze the role of these oxygenases in macrophage- mediated oxidation of LDL under oxidative stress. Upon incubation of LDL with the J-774 A.1 macrophage-like cell line or with human monocyte-derived macrophages (HMDM) in the presence of 1 μmol/L CuSO4, the release of superoxide anions to the medium was demonstrated. Under these conditions, the cytosolic protein components of the NADPH oxidase complex, P-47 and P-67, translocated to the plasma membrane, indicating LDL-mediated activation of the NADPH oxidase complex. Under the above-mentioned experimental conditions, the macrophage 15-lipoxygenase was also activated, as determined by the release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) and 13- hydroxyoctadecadienoic acid (13-HODE) to the medium. Inhibition of the macrophage NADPH oxidase with apocynin or dismutation of superoxide anions, the product of NADPH oxidase activation, with superoxide dismutase (SOD) significantly inhibited macrophage-mediated oxidation of LDL (by 61% to 89%) under these conditions. Phorbol myristate acetate (PMA), which causes NADPH oxidase activation in J-774 A.1 macrophages, had no significant effect on 15- lipoxygenase activity, but still resulted in cell-mediated oxidation of LDL. Finally, HMDM from two patients with chronic granulomatous disease (CGD) that were shown to lack active NADPH oxidase, but to possess almost normal 15- lipoxygenase activity failed to oxidize LDL. We thus conclude that LDL- induced NADPH oxidase activation (under oxidative stress) is required for macrophage-mediated oxidation of LDL, whereas activation of 15-lipoxygenase may not be sufficient for LDL oxidation under these conditions.

Original languageEnglish
Pages (from-to)1069-1079
Number of pages11
JournalMetabolism: Clinical and Experimental
Issue number9
StatePublished - 1 Jan 1996

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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