title: Leukocyte ABCA1 remains atheroprotective in splenectomized LDL receptor knockout mice.
abstract: OBJECTIVE
  ATP-binding cassette transporter A1 (ABCA1) is an important mediator of macrophage cholesterol efflux. It mediates the efflux of cellular cholesterol to lipid-poor apolipoprotein A-I. LDL receptor (LDLr) knockout (KO) mice deficient for leukocyte ABCA1 (ABCA1 KO→LDLr KO) show increased atherosclerosis and splenic lipid accumulation despite largely attenuated serum cholesterol levels. In the present study, we aimed to explore the importance of the spleen for the atheroprotective effects of leukocyte ABCA1.
  
  
  METHODS
  LDLr KO mice were transplanted with bone marrow from ABCA1 KO mice or wild-type (WT) controls. After 8 weeks recovery, mice were either splenectomized (SP-x) or underwent a sham operation, and were subsequently challenged with a Western-type diet (WTD).
  
  
  RESULTS
  In agreement with previous studies, the atherosclerotic lesion area in ABCA1 KO→LDLr KO sham animals (655 ± 82 × 10(3) µm(2)) was 1.4-fold (p = 0.03) larger compared to sham WT→LDLr KO mice (459 ± 33 × 10(3) µm(2)) after 8 weeks WTD feeding, despite 1.7-fold (p<0.001) lower serum cholesterol levels. Interestingly, deletion of ABCA1 in leukocytes led to 1.6-fold higher neutrophil content in the spleen in absence of differences in circulating neutrophils. Levels of KC, an important chemoattractant for neutrophils, in serum, however, were increased 2.9-fold (p = 0.07) in ABCA1 KO→LDLr KO mice. SP-x induced blood neutrophilia as compared to WT→LDLr KO mice (1.9-fold; p<0.05), but did not evoke differences in serum cholesterol and anti-oxLDL antibody levels. Atherosclerotic lesion development, however, was 1.3-fold induced both in the presence and absence of leukocyte ABCA1 (WT: 614 ± 106 × 10(3) µm(2), ABCA1 KO: 786 ± 44 × 10(3) µm(2)). Two-way ANOVA revealed independent effects on atherosclerosis for both leukocyte ABCA1 deficiency and SP-x (p<0.05).
  
  
  CONCLUSIONS
  The observed splenic alterations induced by leukocyte ABCA1 deficiency do not play a significant role in the anti-atherogenic effects of leukocyte ABCA1 on lesion development.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands. b.lammers@lacdr.leidenuniv.nl
authors.forename: Bart
authors.initials: B
authors.lastname: Lammers
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Foks
authors.forename: Reeni B
authors.initials: RB
authors.lastname: Hildebrand
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000097:blood* / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000517:prevention & control; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D007962:Leukocytes / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013156:Splenectomy / Q000379:methods; D014280:Triglycerides / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D008055:Lipids; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D002784:Cholesterol