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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Figure 8

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Effect of BRL49653 on CCR2 expression in freshly isolated human monocyte...
Effect of BRL49653 on CCR2 expression in freshly isolated human monocytes. Freshly isolated human monocytes were cultured in the absence or presence of 1 μM BRL49653 for the indicated time periods. Total RNA was isolated from 106 cells, and 0.5 μg was used for analysis of CCR2 transcripts. (a) The time course of the BRL49653-induced reduction of CCR2 mRNA was analyzed by semiquantitative RT-PCR. As an internal standard, GAPDH was analyzed under identical conditions. (b) CCR2 transcripts of cells cultured for 72 hours in the absence (0 hours) or presence (72 hours) of 1 μM BRL49653 were further analyzed using competitive RT-PCR as described in Figure 7. A dilution factor of 10–8 represents 2,000 molecules of competitor templates in the reaction mix. The point at which both curves intersect indicates that both CCR2 and competitor templates were present at equal concentrations.