Disruption of hedgehog signalling in ApoE − /− mice reduces plasma lipid levels, but increases atherosclerosis due to enhanced lipid uptake by macrophages

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.