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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1558.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Oxidized Low-Density Lipoprotein Correlates Positively With Toll-Like Receptor 2 and Interferon Regulatory Factor-1 and Inversely With Superoxide Dismutase-1 Expression

Studies in Hypercholesterolemic Swine and THP-1 Cells

Paul Holvoet; Penelope C. Davey; Dieuwke De Keyzer; Mory Doukouré; Els Deridder; Marie-Luce Bochaton-Piallat; Giulio Gabbiani; Emmanuel Beaufort; Karine Bishay; Nancy Andrieux; Nora Benhabilès; Gérard Marguerie

From the Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases (P.H., P.C.D., D.D.K., E.D.), Katholieke Universiteit Leuven, Belgium; CliniGenetics (M.D., E.B., K.B., N.A., N.B., G.M.), Nimes, France; and Department of Pathology and Immunology (M.L.B., G.G.), University of Geneva, Switzerland.

Correspondence to Paul Holvoet, PhD, Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Herestraat 49, PB 705, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.be

Background— Oxidized low-density lipoprotein (LDL) is associated with cardiovascular disease. Macrophages contribute to LDL oxidation, and oxidized LDL (oxLDL) affects macrophage function. We searched for the strongest gene correlates of oxLDL in macrophages in coronary plaques and studied the effect of oxLDL on their expression in THP-1 cells.

Methods and Results— Gene expression in macrophages isolated from coronary plaque macrophages from hypercholesterolemic swine was measured on Agilent Human cDNA microarrays. Compared with a universal reference, 1653 transcripts were deregulated. The expression of 11 genes correlated positively and the expression of 5 genes correlated negatively with plaque oxLDL. Interferon regulatory factor-1 (IRF1; R²=0.69) and toll-like receptor 2 (TLR2; R²=0.18) were the strongest positive correlates of oxLDL. Superoxide dismutase 1 (SOD1) was the strongest inverse correlate of oxLDL (R²=0.57). Immunohistochemical analysis showed colocalization of IRF1, TLR2, and SOD1 protein in macrophages and confirmed the RNA expression data. OxLDL-induced foam cell formation in THP-1 macrophages was associated with increased expression of IRF1 and TLR2 and decreased expression of SOD1.

Conclusions— Our data support the hypothesis that oxLDL is a proinflammatory stimulus that induces the expression of TLR2 and IRF1, 2 important gene regulators of innate immune response, and inhibits the expression of the antioxidant SOD1.

We searched for genes of which their expression in macrophages correlates with the complexity and oxidized LDL content of plaques in coronary arteries of hypercholesterolemic swine. Among 1653 deregulated genes, the interferon regulatory factor 1 (IRF1; R²=0.69) and toll-like receptor 2 (TLR2; R²=0.18) were the strongest positive gene correlates of both complexity and oxidized LDL content. Superoxide dismutase 1 (SOD1; R²=0.57) was the strongest inverse correlate of oxLDL. IRF1 and TLR2 protein correlated positively, and SOD1 protein correlated negatively with plaque oxLDL. OxLDL-induced THP-1 foam cell generation was associated with increased IRF1 and TLR2 and decreased SOD1 expression.

Key Words: atherosclerosis • genes • lipoproteins • plaque

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