Role of CXCR7 in Human Coronary Artery Smooth Muscle Restenosis

Abstract

Objective—Whether CXCR7 is a signaling or non-signaling scavenger receptor is still in debate. Our previous study showed that during monocyte-to-macrophage differentiation, CXCR7 mediates positive signaling to the p38 and JNK, but not the ERK1/2 signaling pathways. Here, we studied the expression and signaling function of CXCR7 in human coronary artery smooth muscle cells (HCASMC). Methods and Results—Real-time RT-PCR analysis detected medium level of CXCR7 mRNA expression in HCASMC, which was significantly upregulated by TNFα stimulation. Ligand screening assay found that among all the commercially available CXCR7 ligands, TC14012 was unexpectedly found to inhibit the phosphorylation of ERK1/2 in a time- and dose-dependent manner. This new ERK1/2-inhibitory effect of TC14012 was not due to cell toxicity, and it was not mimicked by CXCR4-selective antagonists, including AMD3100, AMD3645 and IT1t. Since TC14012 is a CXCR4 antagonist and CXCR7 agonist, our data suggest a potential role of CXCR7 in the negative signaling to the ERK1/2 pathway induced by TC14012 in HCASMC. This was supported by the fact that when CXCR4 was blocked by TC14012, SDF-1 switched signaling property from ERK1/2-stimulatory into ERK1/2-inhibitory effect. In addition, we found that TC14012 also suppressed the basal and SDF-1-induced phosphorylation of MEK1, a direct upstream kinase for ERK1/2. Furthermore, we found that TC14012 dose-dependently inhibited HCASMC proliferation induced by 5% FBS, consistent with the well-known cellular function of EKR1/2 signaling pathway. Conclusions—Selective activation of CXCR7 by TC14012 mediates a novel negative signaling to the ERK1/2 MAPK pathway, leading to a suppression of HCASMC proliferation. The finding highlights that CXCR7 may be a new drug target in combating stenosis or re-stenosis coronary artery diseases.