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Macrophage NADPH oxidase activation, impaired cholesterol fluxes, and increased cholesterol biosynthesis in diabetic mice: A stimulatory role for d-glucose

  • Author Footnotes
    1 These authors contributed equally to this work.
    Tony Hayek
    Correspondence
    Corresponding author at: Internal Medicine Department E, Rambam Medical Center, 31096 Haifa, Israel. Tel.: +972 4 854 2059; fax: +972 4 854 2359.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Lipid research Laboratory, Faculty of Medicine, Technion, Rambam Medical Center, Haifa, Israel
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Marielle Kaplan
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Clinical Biochemistry Department, Rambam Medical Center, Haifa, Israel
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  • Rachel Kerry
    Affiliations
    Lipid research Laboratory, Faculty of Medicine, Technion, Rambam Medical Center, Haifa, Israel
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  • Michael Aviram
    Affiliations
    Lipid research Laboratory, Faculty of Medicine, Technion, Rambam Medical Center, Haifa, Israel
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Abstract

      Diabetes is clearly associated with accelerated atherosclerosis development, but molecular mechanisms involved in diabetes-induced atherosclerosis remain to be clarified. The aim of this study was to identify cellular mechanisms involved in diabetes-induced macrophage foam cell formation, the hallmark of early atherogenesis. Mouse peritoneal macrophages (MPMs) isolated from Balb-C streptozotocin-induced diabetic mice, exhibited significantly higher total peroxides, lipid peroxides and paraoxonase 2 (PON2) activity by 290%, 61% and 55%, respectively, compared to non-diabetic mice. In vitro studies revealed that glucose-induced oxidative stress was obtained by d-glucose, but not by l-glucose and it involved activation of the NADPH oxidase complex, and up-regulation of the macrophage PON2.
      Next, MPMs isolated from Balb-C diabetic mice, compared to control Balb-C mice, demonstrated increased cholesterol content by 4.2-fold associated with increased cholesterol biosynthesis and increased uptake of oxidized LDL (Ox-LDL) by 5.9-fold and 31%, respectively. These effects on cellular cholesterol metabolism were associated with up-regulation of the scavenger receptors for Ox-LDL (CD-36 and SR-A), and of HMG-CoA reductase (cholesterol biosynthesis rate limiting enzyme). Finally, using pravastatin (inhibitor of HMG-CoA reductase) and the antioxidant Vitamin E, we have shown that d-glucose-induced macrophage oxidative stress is secondary to its stimulatory effect on macrophage cholesterol biosynthesis.
      In conclusion, macrophages from diabetic mice demonstrate increased oxidative stress associated with activation of NADPH oxidase and up-regulation of cellular PON2, as well as increased macrophages cholesterol uptake and biosynthesis (increased expression of CD-36 and HMG-CoA reductase). The above mechanisms in diabetic mice could be the result of the effect of high d-glucose on macrophages.

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