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.
Beckers
L
L
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands.
Heeneman
S
S
Wang
L
L
Burkly
L C
LC
Rousch
M M J
MM
Davidson
N O
NO
Gijbels
M J J
MJ
de Winther
M P J
MP
Daemen
M J A P
MJ
Lutgens
E
E
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology*; D050197:Atherosclerosis / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D001835:Body Weight; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008055:Lipids / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction
D001057:Apolipoproteins E; D053823:Hedgehog Proteins; D008055:Lipids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein