Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator–activated receptor γ
Ki Hoon Han, … , Christopher K. Glass, Oswald Quehenberger
Ki Hoon Han, … , Christopher K. Glass, Oswald Quehenberger
Published September 15, 2000
Citation Information: J Clin Invest. 2000;106(6):793-802. https://doi.org/10.1172/JCI10052.
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Article

Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator–activated receptor γ

Abstract

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 γ (PPARγ). 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 PPARγ. Modified apoB had no such effect. Consistent with a participation of the PPARγ signaling pathway, BRL49653 reduced CCR2 expression in freshly isolated human monocytes ex vivo and in circulating mouse monocytes in vivo. These results implicate PPARγ in the inhibition of CCR2 gene expression by oxidized lipids, which may help retain monocytes at sites of inflammation, such as the atherosclerotic lesion.

Authors

Ki Hoon Han, Mi Kyung Chang, Agnes Boullier, Simone R. Green, Andrew Li, Christopher K. Glass, Oswald Quehenberger

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Inhibition of THP-1–cell binding of DiO-labeled OxLDL lipids by various ...
Inhibition of THP-1–cell binding of DiO-labeled OxLDL lipids by various competitors. THP-1 cells were incubated for 1 hour at 4°C with microemulsions of DiO-lipids from OxLDL (0.5 μg of phospholipids per milliliter) in the absence (None) or presence of unlabeled lipids from OxLDL (Ox-lipid) at 20 μg phospholipids/mL, apoB from OxLDL (Ox-apoB) at 20 μg/mL, oxidized synthetic PAPC (OxPAPC) at 20 μg/mL phospholipids, and 10 μg/mL neutralizing mouse anti-human CD36 IgM, OKM5. The effect of the various competitors on the binding of DiO-OxLDL lipids was assessed by flow cytometry. All data are expressed as percentage of binding relative to that seen in the absence of competitor (100%) and represent the means ± SD of three independent experiments. The reductions in binding by the various competitors are statistically significant (P < 0.001, unpaired Student’s t test).