Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue
Background—The aim of this study was to determine the role of the chemokine receptor CXCR7 in atherosclerosis and vascular remodeling. CXCR7 is the alternative receptor of CXCL12, which regulates stem cell-mediated vascular repair and limits atherosclerosis via its receptor CXCR4.
Methods and Results—Wire-induced injury of the carotid artery was performed in mice with a ubiquitous, conditional deletion of CXCR7 and in mice treated with the synthetic CXCR7 ligand CCX771. The effect of CCX771 treatment on atherosclerosis was studied in Apoe-/- mice fed a high fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe-/- mice by FPLC. Uptake of DiI-labeled VLDL to adipose tissue was determined by 2-photon microscopy. We show that genetic deficiency of Cxcr7 increased neointima formation and lesional macrophage accumulation in hyperlipidemic mice after vascular injury. This was related to increased serum cholesterol levels and subsequent hyperlipidemia-induced monocytosis. Conversely, administration of the CXCR7 ligand, CCX771, to Apoe-/- mice inhibited lesion formation and ameliorated hyperlipidemia following vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating VLDL levels, but not LDL or HDL levels, and increased uptake of VLDL into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced Angptl4 expression in adipose tissue.
Conclusions—CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected cholesterol-lowering effect of CXCR7 is beneficial for atherosclerotic vascular diseases presumably by ameliorating hyperlipidemia-induced monocytosis and can be augmented using a synthetic CXCR7 ligand.
- Received October 22, 2013.
- Revision received December 16, 2013.
- Accepted December 19, 2013.