Effects of oxidized and glycated LDL on gene expression in human retinal capillary pericytes.

PURPOSE Modified (oxidized and/or glycated) low-density lipoproteins (LDLs) have been implicated in retinal pericyte loss, one of the major pathologic features of early-stage diabetic retinopathy. To delineate underlying molecular mechanisms, the present study was designed to explore the global effects of modified LDL on pericyte gene expression. METHODS Quiescent human retinal pericytes were exposed to native LDL (N-LDL), glycated LDL (G-LDL), and heavily oxidized-glycated LDL (HOG-LDL) for 24 hours, and gene expression was evaluated by DNA microarray analysis. Several of the gene responses were checked, and in each case confirmed by reverse-transcription real-time PCR. RESULTS HOG-LDL induced a gene expression pattern markedly distinct from that of N-LDL or G-LDL, whereas G-LDL elicited gene expression similar to that of N-LDL. A comparison of responses to HOG-LDL versus N-LDL revealed 60 genes with expression that varied by > or =1.7-fold. The HOG-LDL-responsive genes included members of functional pathways, such as fatty acid, eicosanoid, and cholesterol metabolism; fibrinolytic regulation; cell growth and proliferation; cell stress responses; the kinin system; and angiogenesis. CONCLUSIONS HOG-LDL elicits gene expression in retinal pericytes that may contribute to pericyte loss and other retinal abnormalities in diabetic retinopathy. Observed proapoptotic and proangiogenic responses to HOG-LDL may be of particular importance in this regard. The genes identified through these studies provide potential therapeutic targets for the prevention and treatment of diabetic retinopathy.