Independent protective roles for macrophage Abcg1 and Apoe in the atherosclerotic lesion development.
OBJECTIVE
ATP-binding cassette transporter G1 (Abcg1) and apolipoprotein E (Apoe) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. A possible interaction between Abcg1 and Apoe in cholesterol efflux was postulated, but the potential combined action of these proteins on atherosclerotic lesion formation is unclear.


METHODS
LDL receptor knockout (KO) mice were transplanted with bone marrow from Abcg1/Apoe double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls and challenged with a high-fat/high-cholesterol diet for 6 weeks to induce atherosclerosis.


RESULTS
No differences were found in serum lipid levels. The mean atherosclerotic lesion area in dKO transplanted animals (187+/-18x10(3)microm(2)) was 1.4-fold (p<0.01) increased compared to single knockouts (Abcg1 KO: 138+/-5x10(3)microm(2); Apoe KO: 131+/-7x10(3)microm(2)) and 1.9-fold (p<0.001) as compared to WT controls (97+/-15x10(3)microm(2)). In vitro cholesterol efflux experiments established that combined deletion of Abcg1 and Apoe leads to a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts.


CONCLUSIONS
Single deletion of macrophage Abcg1 or Apoe does lead to a moderate non-significant increase in atherosclerotic lesion development as tested by ANOVA, while combined deletion of Abcg1 and Apoe induces a more dramatic and significant increase in atherosclerosis. Our results indicate an additive, independent effect for both macrophage Abcg1 and Apoe in the prevention of atherosclerosis.
Lammers
Bart
B
Gorlaeus Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands. b.lammers@lacdr.leidenuniv.nl
Out
Ruud
R
Hildebrand
Reeni B
RB
Quinn
Carmel M
CM
Williamson
David
D
Hoekstra
Menno
M
Meurs
Illiana
I
Van Berkel
Theo J C
TJ
Jessup
Wendy
W
Van Eck
Miranda
M
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological
C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D008074:Lipoproteins; D002784:Cholesterol