Ligands for peroxisome proliferator-activated receptor inhibit monocyte CCR2 expression stimulated by plasma lipoproteins

Abstract

Substantial evidence supports a causal role for monocyte chemoattractant protein-1 (MCP-1) and its receptor, CCR2, in the recruitment of monocytes from the circulation into atherosclerotic lesions. MCP-1 is produced and secreted by virtually every cellular component of the vessel wall. It generally is assumed that the magnitude of the monocyte chemotactic activity, which is initiated by the functional activation of CCR2 by MCP-1, is directly proportional to the concentration of the chemoattractant. However, we recently demonstrated that an inflammatory response of monocytes is finely regulated and also depends on the expression levels of CCR2. We identified plasma low-density lipoprotein (LDL) as a positive regulator and showed that it greatly increased monocyte CCR2 gene expression. In contrast, activation of peroxisome proliferator-activated receptor by synthetic ligands or components of oxidized LDL reduces monocyte CCR2 expression and blocks chemotaxis mediated by MCP-1. We hypothesized that the excessive monocyte accumulation in the vessel wall during atherogenesis may result in part from an enhanced chemotactic response. These findings suggest CCR2 gene expression in circulating monocytes as a potential additional target for intervention and prevention of atherosclerosis.