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.
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.


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.
Holvoet
Paul
P
Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Herestraat 49, PB 705, B-3000 Leuven, Belgium. paul.holvoet@med.kuleuven.be
Davey
Penelope C
PC
De Keyzer
Dieuwke
D
Doukouré
Mory
M
Deridder
Els
E
Bochaton-Piallat
Marie-Luce
ML
Gabbiani
Giulio
G
Beaufort
Emmanuel
E
Bishay
Karine
K
Andrieux
Nancy
N
Benhabilès
Nora
N
Marguerie
Gérard
G
D000368:Aged; D000818:Animals; D002460:Cell Line; D003324:Coronary Artery Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000378:metabolism*; D007150:Immunohistochemistry; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013552:Swine; D013556:Swine, Miniature; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D050856:Interferon Regulatory Factor-1; D008077:Lipoproteins, LDL; C000606290:SOD1 protein, human; D051195:Toll-Like Receptor 2; C099252:oxidized low density lipoprotein; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1