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@PHDTHESIS{Li:228721,
author = {Li, Xiaofeng},
othercontributors = {Schober, Andreas},
title = {{A}ctivation of {CXCR}7 improves hyperlipidemia by
increasing cholesterol storage in adipose tissue and limits
atherosclerosis},
address = {Aachen},
publisher = {Publikationsserver der RWTH Aachen University},
reportid = {RWTH-CONV-143889},
pages = {VI, 104 S. : Ill., graph. Darst.},
year = {2013},
note = {Aachen, Techn. Hochsch., Diss., 2013},
abstract = {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.},
keywords = {Arteriosklerose (SWD) / Chemokine (SWD)},
cin = {531010-4 / 160000},
ddc = {570},
cid = {$I:(DE-82)531010-4_20140620$ / $I:(DE-82)160000_20140620$},
typ = {PUB:(DE-HGF)11},
urn = {urn:nbn:de:hbz:82-opus-47739},
url = {https://publications.rwth-aachen.de/record/228721},
}
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