Augmented atherogenesis in LDL receptor deficient mice lacking both macrophage ABCA1 and ApoE.
OBJECTIVE
ABCA1 protects against atherosclerosis by facilitating cholesterol efflux from macrophage foam cells in the arterial wall to extracellular apolipoprotein (apo) A-I. In contrast to apoA-I, apoE is secreted by macrophages and can, like apoA-I, induce ABCA1-mediated cholesterol efflux. Yet, the combined effect of macrophage ABCA1 and apoE on lesion development is unexplored.


RESULTS
LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/apoE double KO (dKO) mice, their respective single KO's, and wild-type (WT) controls and were challenged with a high-fat/high-cholesterol diet for 9 weeks. In vitro cholesterol efflux experiments showed no differences between ABCA1 KO and dKO macrophages. The serum non-HDL/HDL ratio in dKO transplanted mice was 1.7-fold and 2.4-fold (p<0.01) increased compared to WT and ABCA1 KO transplanted mice, respectively. The atherosclerotic lesion area in dKO transplanted animals (650±94×10(3) µm(2)), however, was 1.9-fold (p<0.01) and 1.6-fold (p<0.01) increased compared to single knockouts (ABCA1 KO: 341±20×10(3) µm(2); apoE KO: 402±78×10(3) µm(2), respectively) and 3.1-fold increased (p<0.001) compared to WT (211±20×10(3) µm(2)). When normalized for serum cholesterol exposure, macrophage ABCA1 and apoE independently protected against atherosclerotic lesion development (p<0.001). Moreover, hepatic expression levels of TNFα and IL-6 were highly induced in dKO transplanted animals (3.0-fold; p<0.05, and 4.3-fold; p<0.001, respectively). In agreement, serum IL-6 levels were also enhanced in ABCA1 KO transplanted mice (p<0.05) and even further enhanced in dKO transplanted animals (3.1-fold as compared to ABCA1 KO transplanted animals; p<0.05).


CONCLUSIONS
Combined deletion of macrophage ABCA1 and apoE results in a defect in cholesterol efflux and, compared to ABCA1 KO transplanted mice, elevated serum total cholesterol levels. Importantly, these mice also suffer from enhanced systemic and hepatic inflammation, together resulting in the observed augmented atherosclerotic lesion development.
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands. b.lammers@lacdr.leidenuniv.nl
Bart
B
Lammers
Ying
Y
Zhao
Menno
M
Hoekstra
Reeni B
RB
Hildebrand
Dan
D
Ye
Illiana
I
Meurs
Theo J C
TJ
Van Berkel
Miranda
M
Van Eck
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000172:deficiency*; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002788:Cholesterol Esters / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D002788:Cholesterol Esters; D016207:Cytokines; D004041:Dietary Fats; D018836:Inflammation Mediators; D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D008071:Lipoprotein Lipase