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

• Published in: The Journal of pathology Vol. 212; no. 4; pp. 420 - 428
• Main Authors: Beckers, L, Heeneman, S, Wang, L, Burkly, LC, Rousch, MMJ, Davidson, NO, Gijbels, MJJ, de Winther, MPJ, Daemen, MJAP, Lutgens, E
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2007; Wiley
• Subjects: Aged; Aged, 80 and over; Animals; Apolipoproteins E - deficiency; Apolipoproteins E - physiology; atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - blood; Atherosclerosis - pathology; Atherosclerosis - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Body Weight; Cardiology. Vascular system; Cells, Cultured; Disease Models, Animal; Female; hedgehog; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - physiology; Humans; Investigative techniques, diagnostic techniques (general aspects); lipids; Lipids - blood; Lipoproteins, LDL - blood; Macrophages - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Signal Transduction; Rodentia; Cardiovascular disease; Lipids; Increase; Uptake; Blood plasma; Vascular disease; Vertebrata; Anatomic pathology; Mammalia; Mouse; hedgehog; Apolipoprotein E; Hedgehog protein; Animal; Atherosclerosis; Macrophage
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2193

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.