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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1137.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

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

From the Division of Inflammation Biology (C.A.G., K.L.), La Jolla Institute for Allergy & Immunology, La Jolla, Calif; Robert M. Berne Cardiovascular Research Center (J.M.S.) and the Department of Endocrinology and Metabolism (J.N.), University of Virginia, Charlottesville.

Correspondence to Christian A. Gleissner, MD, Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, 9420 Athena Circle Drive, La Jolla, CA 92037. E-mail christian{at}liai.org

Abstract

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.

Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway, which is linked to microvascular complications in diabetes. Upregulation of AR gene expression and activity in macrophages during foam cell formation resulted in increased oxidative stress. AR expression in macrophages in human atherosclerotic lesions supports its role in atherogenesis.

Key Words: atherosclerosis • diabetes mellitus • lipoproteins • macrophage • plaque