Upregulation of aldose reductase during foam cell formation as possible link among diabetes, hyperlipidemia, and atherosclerosis

Christian A. Gleissner, John M. Sanders, Jerry Nadler, Klaus Ley

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


Objective-Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway. In diabetes, it is related to microvascular complications. We discovered AR expression in foam cells by gene chip screening and hypothesized that it may be relevant in atherosclerosis. Methods and Results-AR gene expression and activity were found to be increased in human blood monocyte-derived macrophages during foam cell formation induced by oxidized LDL (oxLDL, 100 μg/mL). AR activity as photometrically determined by NADPH consumption was effectively inhibited by the AR inhibitor epalrestat. oxLDL-dependent AR upregulation was further increased under hyperglycemic conditions (30 mmol/L D-glucose) as compared to osmotic control, suggesting a synergistic effect of hyperlipidemia and hyperglycemia. AR was also upregulated by 4-hydroxynonenal, a constituent of oxLDL. Upregulation was blocked by an antibody to CD36. AR inhibition resulted in reduction of oxLDL-induced intracellular oxidative stress as determined by 2'7'-dichlorofluoresceine diacetate (H2DCFDA) fluorescence, indicating that proinflammatory effects of oxLDL are partly mediated by AR. Immunohistochemistry showed AR expression in CD68+ human atherosclerotic plaque macrophages. Conclusions-These data show that oxLDL-induced upregulation of AR in human macrophages is proinflammatory in foam cells and may represent a potential link among hyperlipidemia, atherosclerosis, and diabetes mellitus.

Original languageEnglish (US)
Pages (from-to)1137-1143
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number6
StatePublished - Jun 1 2008
Externally publishedYes


  • Atherosclerosis
  • Diabetes mellitus
  • Lipoproteins
  • Macrophage
  • Plaque

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Upregulation of aldose reductase during foam cell formation as possible link among diabetes, hyperlipidemia, and atherosclerosis'. Together they form a unique fingerprint.

Cite this