Unstable atherosclerotic plaques are prone to rupture, which leads to atherothrombosis. Endothelial progenitor cells (EPCs) are bone marrow (BM)-derived precursor cells that may repair vascular injury in atherosclerosis. Chemokine (C-C motif) receptor 5 (CCR5) promotes mobilization of EPCs. In this study, we investigated the therapeutic potential of CCR5 overexpressing EPCs on plaques stabilization in apolipoprotein E (ApoE)(-/-) mouse model.
The expression of CCR5 and its cognate ligand chemokine (C-C motif) ligand 5 (CCL5) were examined in atherosclerotic aortas of human and mice by immunohistochemistry. Splenectomized ApoE(-/-) C57BL/6 J mice fed with high-fat diet for 24 weeks were intravenously injected with EPCs transfected with CCR5 overexpression lentivirus. The recruitment of EPCs over the atherosclerotic plaques was evaluated by immunofluorescence. The content of lipid, smooth muscle cells, monocytes/macrophages, and endothelial cells in atherosclerotic plaques were assayed by specific immunostaining. The serum levels of atherosclerosis-related inflammatory factors in ApoE(-/-) mice were measured by a mouse atherosclerosis antibody array I.
CCR5 and CCL5 are highly expressed in atherosclerotic plaques in both human and mice. The ApoE(-/-) mice with CCR5 overexpressing EPC treatment demonstrated a more stability plaques formation with enhanced recruitment of EPCs, reduced lipids and macrophages content in the atherosclerotic plaques. CCR5 overexpressing EPCs treatment also increased the content of endothelial cells and nitric oxide (NO) production in the plaques. In addition, the serum levels of interleukin 3 (IL-3), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 13(IL-13), CD40 and tumor necrosis factor-alpha (TNF-alpha), and the plaques contents of IL-6 and matrix metalloproteinase 9 (MMP9) were reduced in mice with CCR5 overexpressing EPC treatment.
These findings suggest that CCR5 is a novel therapeutic target in EPC treatment for stabilization of atherosclerotic plaques.