Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue

Abstract

C hemokines, acting through various mechanisms including the recruitment of immune cells and smooth muscle progenitor cells (SPCs) to the vessel wall, 1,2 are crucial for vascular remodeling and atherosclerosis. In addition, chemokines are critical for monocyte and neutrophil homeostasis. Hyperlipidemia-induced monocytosis results from the combined action of various chemokine receptors, such as CCR2, which are expressed by immune cells (including monocytes), and facilitates atherosclerosis.3-5 By contrast, the CXCL12 receptor, CXCR4, protects against atherosclerosis by controlling the mobilization of neutrophils, 6 whereas the mobilization and recruitment of SPCs by CXCL12 during vascular repair aggravates neointima formation, which indicates a contextspecific role for this chemokine-receptor axis in arterial remodeling.7,8 Accordingly, increased levels of CXCL12 and SPCs are observed in patients with severe cardiac allograft vasculopathy.9 Systemic treatment with CXCL12 induces the release of SPCs, which accumulate in atherosclerotic lesions and thus lead to plaque stabilization. 10 Whereas most of the effects of CXCL12 are linked to its interaction with CXCR4, the function of the alternative CXCL12 receptor, CXCR7, in atherogenesis and vascular remodeling is unclear. Clinical Perspective on p 1253Background-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 apolipoprotein E-deficient (Apoe) mice fed a high-fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe −/− mice by fast protein liquid chromatography. Uptake of DiI-labeled very low-density lipoprotein 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 after vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating very lowdensity lipoprotein levels but not low-density lipoprotein or high-density lipoprotein levels and increased uptake of very low-density lipoprotein into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced expression of Angptl4 in adipose tissue. Conclusions-CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected choleste...

Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

“…Induction of chemokine receptor CXCR7 expression, expressed predominantly in endothelial cells, promotes liver repair and limits atherosclerosis 23,38 . Thus, we examined CXCR7 expression in PCECs.…”

Chemokines in Atherosclerosis

“…Conversely, chemokine receptors have been found to directly regulate lipid levels and hyperlipidemia-induced inflammation, for example, modulating very-low-density lipoprotein receptor uptake. 29 Notably, atherosclerosis progression has recently been shown to not solely rely on a continued influx of newly recruited monocytes. Whereas monocyte recruitment and differentiation is important in early lesion formation, lesional macrophages proliferate to locally augment their numbers in plaques at later stages.…”

“…[63][64][65] By conditional knockout of CXCR7 and use of the synthetic agonist ligand CCX771, recent studies revealed that CXCR7 reduced atherosclerotic lesion formation, lowering hyperlipidemia and subsequent monocytosis. 29 Not expressed on leukocytes, CXCR7 in adipocytes regulated blood cholesterol by promoting very-low-density lipoprotein uptake in adipose tissue, associated with an enhanced lipase activity and reduced angiopoietin-like protein 4 expression. In contrast, the relevance of chemokine-scavenging receptors to atherogenic mobilization and recruitment of inflammatory cells remains to be addressed.…”

The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease

“…In this context, the CXCR7 agonist CCX771 was recently shown to increase the uptake of very low-density LDL (VLDL) in adipocytes. Correspondingly, treatment of Apoe −/− mice with CCX771 reduced the levels of circulating VLDL and decreased atherosclerosis (Li et al, 2014). Whether similar mechanisms can be identified in other cell types as macrophages remains to be examined, as are the exact mechanisms underlying CXCR7-mediated uptake of VLDL or modified lipids.…”