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


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 microg/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.
Gleissner
Christian A
CA
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, 9420 Athena Circle Drive, La Jolla, CA 92037, USA. christian@liai.org
Sanders
John M
JM
Nadler
Jerry
J
Ley
Klaus
K
D000328:Adult; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000494:pharmacology; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000201:enzymology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology; D012236:Rhodanine / Q000031:analogs & derivatives / Q000494:pharmacology; D012307:Risk Factors; D053778:Thiazolidines / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000447:Aldehydes; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D053778:Thiazolidines; C099252:oxidized low density lipoprotein; C038131:epalrestat; D012236:Rhodanine; D000449:Aldehyde Reductase; C027576:4-hydroxy-2-nonenal