Oxidized low-density lipoprotein-induced expression of ABCA1 in blood monocytes precedes coronary atherosclerosis and is associated with plaque complexity in hypercholesterolemic pigs.
BACKGROUND
Elevated oxidized low-density lipoprotein (oxLDL) is associated with atherosclerosis and high cardiovascular risk. Previously, we identified 18 genes in coronary plaque macrophages of hypercholesterolemic pigs that correlated with plaque oxLDL.


OBJECTIVE
To determine which of these genes were differentially expressed in blood monocytes and correlated with blood and plaque oxLDL and with plaque complexity.


METHODS
RNA expression in monocytes of 27 hypercholesterolemic and 12 control pigs was analyzed with quantitative real-time polymerase chain reaction.


RESULTS
Five of 12 genes with detectable expression in monocytes were overexpressed (at P < 0.01 level) in blood monocytes of hypercholesterolemic pigs: ABCA1, SCD, IRF1, SDC2, and TLR2. ABCA1 RNA expression in blood monocytes correlated with blood oxLDL, and its RNA and protein expression was increased prior to atherosclerotic plaque formation. Higher expression of ABCA1 in monocytes was associated with higher plaque complexity and higher plaque oxLDL. Immunostaining of coronary plaques showed the association of ABCA1 with macrophages, lipids, and oxLDL; ABCA1 protein correlated with plaque oxLDL (R(2) = 0.66; P < 0.0001). In THP-1 monocytes, oxLDL induced ABCA1 expression. OxLDL-induced foam cell generation in THP-1 and human monocyte-derived macrophages was associated with a further increase of ABCA1 expression.


CONCLUSIONS
The increase of ABCA1 in monocytes in association with blood oxLDL prior to atherosclerotic lesion formation and the association of higher ABCA1 with higher plaque complexity suggests that ABCA1 is an early biomarker of atherosclerosis. Studies in humans are warranted.
Geeraert
B
B
Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium.
De Keyzer
D
D
Davey
P C
PC
Crombé
F
F
Benhabilès
N
N
Holvoet
P
P
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000097:blood*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D013230:Stearoyl-CoA Desaturase