h1

%0 Thesis
%A Li, Xiaofeng
%T Activation of CXCR7 improves hyperlipidemia by increasing cholesterol storage in adipose tissue and limits atherosclerosis
%C Aachen
%I Publikationsserver der RWTH Aachen University
%M RWTH-CONV-143889
%P VI, 104 S. : Ill., graph. Darst.
%D 2013
%Z Aachen, Techn. Hochsch., Diss., 2013
%X The results of the current study show that the loss of Cxcr7 expression in Apoe-/- mice enhanced neointima formation after vascular injury. Increased neointimal hyperplasia in the absence of Cxcr7 is associated with increased macrophage accumulation in the neointima. The latter effect can be attributed to elevated serum cholesterol and triglyceride levels, which may promote hyperlipidemia-induced monocytosis. However, Cxcr7 deficiency did not alter the SPC mobilization after vascular injury, suggesting that the Cxcl12 gradient still exists due to the finding that the levels of this chemokine in the bone marrow and blood are simultaneously elevated. Unlike Cxcr7 deficiency in Apoe-/- mice, Cxcr7 deficiency in Apoe+/+ mice fed a HCD did not exacerbate neointima formation or affect lipid levels and monocytosis after vascular injury, indicating that hyperlipidemia is required for the effects of Cxcr7 on neointima formation. Moreover, deficiency of Cxcr7 only in bone marrow cells had no effect on neointima formation, which makes a role of Cxcr7 on leukocytes in lesion formation unlikely. In contrast to the effect of Cxcr7 deficiency, administration of the Cxcr7 ligand CCX771 in Apoe-/- mice inhibited neointima formation. In addition, CCX771 reduced cholesterol and triglyceride levels, and diminished monocytosis. Moreover, removal of spleen did not reverse the effects of CCX771 on neointima formation, excluding an important role of splenic Cxcr7 expression in neointima formation. Given the cholesterol-lowing effect of CCX771, this study further investigated the effect of CCX771 in diet-induced atherosclerosis and found that CCX771 treatment ameliorated lesion formation and hyperlipidemia in diet-induced atherosclerosis. Of note, CCX771 treatment did not result in any obvious toxicity. Lipid profiling analysis further demonstrated that CCX771 treatment preferentially down-regulates VLDL levels without affecting LDL and HDL levels. This study showed that CCX771 treatment increased the cholesterol levels and the uptake of VLDL into adipocytes. However, CCX771 treatment did not alter the cholesterol levels and the uptake of VLDL in the liver. Moreover, endothelial-specific Cxcr7 deficiency failed to increase the cholesterol levels and promote monoytosis. Therefore, the reduced circulating VLDL levels by CCX771 treatment could be attributable to the increased uptake of VLDL into Cxcr7-expressing adipocytes. Thus, the data of the current study indicate that Cxcr7 regulates blood cholesterol levels by promoting its storage in adipocytes. In conclusion, this study suggests a key role of Cxcr7 in controlling vascular neointima formation and the development of atherosclerosis. Cxcr7 activation promotes the uptake of VLDL into adipose tissues and decreases the blood cholesterol levels, especially VLDL cholesterol levels. As a consequence, Cxcr7 activation ameliorates hyperlipidemia and hyperlipidemia-induced monocytosis. The combined down regulation of cholesterol levels and peripheral monocyte counts might not only cause a reduction in the number of monocytes entering into vascular wall, but also reduce the differentiation from monocytes to macrophages. Reduced accumulation of macrophages may reduce the progression of neointimal hyperplasia and the formation of atherosclerotic plaques. CCX771, a Cxcr7 ligand, could potentiate the athero-protective effects of Cxcr7. Accordingly, this unexpected cholesterol-lowering effect of Cxcr7 may be beneficial in atherosclerotic vascular diseases and can be therapeutically augmented using a synthetic Cxcr7 ligand, CCX771.
%K Arteriosklerose (SWD)
%K Chemokine (SWD)
%F PUB:(DE-HGF)11
%9 Dissertation / PhD Thesis
%U https://publications.rwth-aachen.de/record/228721