Abstract
AimATP-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.MethodsLDLr 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).ResultsIn agreement with previous studies, the atherosclerotic lesion area in ABCA1 KO→LDLr KO sham animals (655±82×103 µm2) was 1.4-fold (p = 0.03) larger compared to sham WT→LDLr KO mice (459±33×103 µm2) 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±106×103 µm2, ABCA1 KO: 786±44×103 µm2). Two-way ANOVA revealed independent effects on atherosclerosis for both leukocyte ABCA1 deficiency and SP-x (p<0.05).ConclusionsThe 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.
Highlights
Reverse cholesterol transport (RCT) is an important mechanism by which HDL and its major apolipoprotein A-I protect against atherosclerosis. [1] In this process, the cellular cholesterol efflux machinery is essential to maintain cellular lipid homeostasis in macrophages and to prevent pathological foam cell formation, a hallmark of atherosclerosis
In agreement with previous studies, the atherosclerotic lesion area in ATP-binding cassette transporter A1 (ABCA1) KORLDLr KO sham animals (6556826103 mm2) was 1.4-fold (p = 0.03) larger compared to sham WTRLDLr KO mice (4596336103 mm2) after 8 weeks Western-type diet (WTD) feeding, despite 1.7-fold (p,0.001) lower serum cholesterol levels
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
Summary
Reverse cholesterol transport (RCT) is an important mechanism by which HDL and its major apolipoprotein A-I (apoA-I) protect against atherosclerosis. [1] In this process, the cellular cholesterol efflux machinery is essential to maintain cellular lipid homeostasis in macrophages and to prevent pathological foam cell formation, a hallmark of atherosclerosis. [3,4] Deficiency of leukocyte ABCA1 on the LDLr KO background (ABCA1 KORLDLr KO) led to increased atherosclerosis, despite largely attenuated cholesterol levels. The spleen is the largest lymphoid organ in the body with important immunological functions. It produces antibodies, facilitates phagocytosis and is capable of eliminating foreign antigens. To investigate the possible interplay between the spleen and leukocyte ABCA1 with respect to the development of atherosclerosis, we transplanted bone marrow from ABCA1 deficient mice into LDLr deficient recipient mice, which were subsequently either splenectomized or underwent a sham operation. Our results show that leukocyte ABCA1 deficiency resulted in decreased TC levels, increased inflammation, and lipid and neutrophil accumulation in the spleen. The observed splenic alterations induced by leukocyte ABCA1 deficiency did not alter anti-oxLDL antibody levels, nor played a significant role in atherosclerotic lesion development as evidenced by splenectomy
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