Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor gamma.
The CCR2-mediated recruitment of monocytes into the vessel wall plays an important role in all stages of atherosclerosis. In recent studies, we have shown that lipoproteins can modulate CCR2 expression and have identified native LDL as a positive regulator. In contrast, oxidized LDL (OxLDL), which is mainly formed in the aortic intima, reduces CCR2 expression, promotes monocyte retention, and may cause pathological accumulation of monocytes in the vessel wall. We now provide evidence that OxLDL reduces monocyte CCR2 expression by activating intracellular signaling pathways that may involve peroxisome proliferator-activated receptor gamma (PPARgamma). Receptor-mediated uptake of the lipoprotein particle was required and allows for delivery of the exogenous ligand to the nuclear receptor. The suppression of CCR2 expression by OxLDL was mediated by lipid components of OxLDL, such as the oxidized linoleic acid metabolites 9-HODE and 13-HODE, known activators of PPARgamma. Modified apoB had no such effect. Consistent with a participation of the PPARgamma signaling pathway, BRL49653 reduced CCR2 expression in freshly isolated human monocytes ex vivo and in circulating mouse monocytes in vivo. These results implicate PPARgamma in the inhibition of CCR2 gene expression by oxidized lipids, which may help retain monocytes at sites of inflammation, such as the atherosclerotic lesion.
Han
K H
KH
Department of Medicine, University of California at San Diego, La Jolla, California 92093-0682, USA.
Chang
M K
MK
Boullier
A
A
Green
S R
SR
Li
A
A
Glass
C K
CK
Quehenberger
O
O
D000818:Animals; D001055:Apolipoproteins B / Q000494:pharmacology; D001161:Arteriosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism / Q000494:pharmacology; D008041:Linoleic Acids / Q000378:metabolism; D044243:Linoleic Acids, Conjugated; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*
D001055:Apolipoproteins B; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D008041:Linoleic Acids; D044243:Linoleic Acids, Conjugated; D008077:Lipoproteins, LDL; D010743:Phospholipids; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D000077154:Rosiglitazone; C024347:9-hydroxy-10,12-octadecadienoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; D019787:Linoleic Acid