Lipid-free apolipoprotein A-I and discoidal reconstituted high-density lipoproteins differentially inhibit glucose-induced oxidative stress in human macrophages

Fatiha Tabet*, Gilles Lambert, Luisa F. Cuesta Torres, Liming Hou, Irene Sotirchos, Rhian M. Touyz, Alicia J. Jenkins, Philip J. Barter, Kerry-Anne Rye

*Corresponding author for this work

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31 Citations (Scopus)

Abstract

Objective- The goal of this study was to investigate the mechanisms by which apolipoprotein (apo) A-I, in the lipid-free form or as a constituent of discoidal reconstituted high-density lipoproteins ([A-I]rHDL), inhibits high-glucose-induced redox signaling in human monocyte-derived macrophages (HMDM). Methods and Results- HMDM were incubated under normal (5.8 mmol/L) or high-glucose (25 mmol/L) conditions with native high-density lipoproteins (HDL) lipid-free apoA-I from normal subjects and from subjects with type 2 diabetes (T2D) or (A-I)rHDL. Superoxide (O2-) production was measured using dihydroethidium fluorescence. NADPH oxidase activity was assessed using lucigenin-derived chemiluminescence and a cyotochrome c assay. p47phox translocation to the plasma membrane, Nox2, superoxide dismutase 1 (SOD1), and SOD2 mRNA and protein levels were determined by real-time polymerase chain reaction and Western blotting. Native HDL induced a time-dependent inhibition of O2- generation in HMDM incubated with 25 mmol/L glucose. Lipid-free apoA-I and (A-I)rHDL increased SOD1 and SOD2 levels and attenuated 25 mmol/L glucose-mediated increases in cellular O2-, NADPH oxidase activity, p47 translocation, and Nox2 expression. Lipid-free apoA-I mediated its effects on Nox2, SOD1, and SOD2 via ABCA1. (A-I)rHDL-mediated effects were via ABCG1 and scavenger receptor BI. Lipid-free apoA-I from subjects with T2D inhibited reactive oxygen species generation less efficiently than normal apoA-I. Conclusion- Native HDL, lipid-free apoA-I and (A-I)rHDL inhibit high-glucose-induced redox signaling in HMDM. The antioxidant properties of apoA-I are attenuated in T2D.

Original languageEnglish
Pages (from-to)1192-1200
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number5
DOIs
Publication statusPublished - 1 May 2011
Externally publishedYes

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Keywords

  • diabetes mellitus
  • HDL
  • lipoproteins
  • macrophages
  • reactive oxygen species

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