OxLDL induces expression and activity of aldose reductase in human monocyte‐derived macrophages

Abstract

Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway, which utilizes excess glucose and reduces it to sorbitol and fructose. AR activity in diabetics has been associated with retinopathy, nephropathy, and neuropathy. Furthermore, human AR has been shown to increase atherosclerotic lesions if overexpressed in ApoE−/− mice. We measured gene expression in human peripheral blood mononuclear cells (PBMCs), monocytes and macrophages as well as foam cells induced by native LDL, mmLDL or oxLDL using 22 Affymetrix gene chips (HG-U133A). Statistical analysis was performed using local pooled error test (LPE) and heteregenous error model (HEM). A significant increase of AR gene expression could be demonstrated in macrophageas after 48 hours of treatment with oxLDL and mmLDL, however not with LDL. Simultaneously, several genes associated with increased oxidative stress were upregulated (e.g. genes of the glutathione or thioredoxin system or metallothioneins). Upregulation of AR by oxLDL was confirmed by real-time PCR. Furthermore, an increase of AR enzyme activity could be shown as measured by increased NADPH consumption. oxLDL-induced AR activity was absent when macrophages were treated with the AR inhibitor epalrestat. We hypothesize that oxLDL-induced expression of AR in foam cells represents a novel pro-inflammatory mechanism and a potentially relevant therapeutic target in atherosclerosis.