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Disruption of hedgehog signalling in ApoE − /− mice reduces plasma lipid levels, but increases atherosclerosis due to enhanced lipid uptake by macrophages
Author(s) -
Beckers L,
Heeneman S,
Wang L,
Burkly LC,
Rousch MMJ,
Davidson NO,
Gijbels MJJ,
de Winther MPJ,
Daemen MJAP,
Lutgens E
Publication year - 2007
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2193
Subject(s) - foam cell , hedgehog signaling pathway , hedgehog , oil red o , macrophage , medicine , endocrinology , sonic hedgehog , morphogen , chemistry , biology , microbiology and biotechnology , cholesterol , signal transduction , lipoprotein , biochemistry , in vitro , adipose tissue , adipogenesis , gene
Embryonic pathways are often re‐expressed in adult pathology. Here we investigated the role of the morphogen hedgehog (hh), which we found to be re‐expressed in atherosclerotic plaques. Male ApoE − /− mice were treated for 12 weeks with an anti‐hh antibody (5E1) or a control IgG (1E6) starting at the age of 6 or 18 weeks. Inhibition of hh signalling induced a significant increase in total plaque area in the aortic arch, a result of an increase (54% and 36%, respectively) in the area of advanced plaques (atheromata). In mice treated with anti‐hh, plaques contained large (18–35% > ctrl), lipid‐filled, sometimes multinucleated macrophage foam cells. Plasma cholesterol levels decreased after anti‐hh treatment. In bone marrow‐derived macrophages, foam cell formation was enhanced after inhibition of hh signalling. Anti‐hh treatment caused a 54–75% increase in early oxLDL uptake (10–240 min), which was scavenger receptor‐mediated. After 3–24 h of oxLDL incubation, intense Oil red O staining as well as increased amounts of cholesterol esters were present in these macrophages after anti‐hh treatment. Activation of the HH‐signalling cascade by recombinant Shh induced a decrease in oxLDL uptake. Here we show that the hh‐signalling pathway is one of the morphogenic pathways that regulate plasma lipid levels and atherosclerosis development and progression. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.