BACKGROUND AND AIMS\nMETHODS\nRESULTS\nCONCLUSIONS\nThere is extensive evidence from bone marrow transplantation studies that hematopoietic ATP binding cassette A1 (Abca1) is atheroprotective in... Show moreBACKGROUND AND AIMS\nMETHODS\nRESULTS\nCONCLUSIONS\nThere is extensive evidence from bone marrow transplantation studies that hematopoietic ATP binding cassette A1 (Abca1) is atheroprotective in low-density lipoprotein receptor (Ldlr) deficient mice. In contrast, studies using lysosyme M promoter-driven deletion of Abca1 in Ldlr deficient mice failed to show similar effects. It was hypothesized that the discrepancy between these studies might be due to the presence of Ldlr in bone marrow-derived cells in the transplantation model. In this study, we aim to determine the contribution of Ldlr to the atheroprotective effect of hematopoietic Abca1 in the murine bone marrow transplantation model.\nWild-type, Ldlr-/-, Abca1-/-, and Abca1-/-Ldlr-/- bone marrow was transplanted into hypercholesterolemic Ldlr-/- mice.\nBone marrow Lldr deficiency did not influence the effects of Abca1 on macrophage cholesterol efflux, foam cell formation, monocytosis or plasma cholesterol. Ldlr deficiency did reduce circulating and peritoneal lymphocyte counts, albeit only in animals lacking Abca1 in bone marrow-derived cells. Importantly, the effects of Abca1 deficiency on atherosclerosis susceptibility were unaltered by the presence or absence of Ldlr. Bone marrow Ldlr deficiency did lead to marginally but consistently decreased atherosclerosis, regardless of Abca1 deficiency. Thus, Ldlr expression on bone marrow-derived cells does, to a minimal extent, influence atherosclerotic lesion development, albeit independent of Abca1.\nThis study provides novel insight into the relative impact of Ldlr and Abca1 in bone marrow-derived cells on macrophage foam cell formation and atherosclerosis development in vivo. We have shown that Ldlr and Abca1 differentially and independently influence atherosclerosis development in a murine bone marrow transplantation model of atherosclerosis. Show less
Snip, O.S.C.; Hoekstra, M.; Zhao, Y.; Calpe-Berdiel, L.; Vulve, J.; Carles Escola-Gil, J.; ... ; Eck, M. van 2018
Various studies have shown that leukocyteATP-binding cassette transporter A1 (ABCA1) is an anti-atherogenic factor. It has long been assumed that the increased atherosclerosis susceptibility... Show moreVarious studies have shown that leukocyteATP-binding cassette transporter A1 (ABCA1) is an anti-atherogenic factor. It has long been assumed that the increased atherosclerosis susceptibility observed in leukocyte ABCA1 deficient hyperlipidemic mice was due to an accelerated foam cell formation. However, several studies have suggested that leukocyte ABCA1 may also have a beneficial effect on systemic inflammation. In this study we aim to determine the effect of leukocyte ABCA1 deficiency on atherosclerosis susceptibility in mice that are apolipoprotein A1 (apoA1) deficient.To determine the impact of leukocyte ABCA1 on atherosclerosis outcome, lethally irradiated low-density lipoprotein receptorknock-out (sKO) mice or LDLr/apoA1 double KO (dKO) mice were reconstituted with either ABCA1 KO or wild-type bone marrow. All four groups of chimeric mice were fed a Western-type diet for 6 weeks to induce atherosclerotic lesion development.Leukocyte ABCA1 deficiency in dKO mice resulted in 50-70% larger lesions in the aortic root than those observed in both sKO mice transplanted with ABCA1 KO bone marrow and dKO mice transplanted with wild-type bone marrow. Furthermore, total leukocyte numbers in blood were generally higher in mice lacking apoA1 as compared to those containing apoA1-carrying HDL particles. Two way ANOVA on the different white blood cell sub-populations suggested that the apoA1 deficiency-associated increase in total leukocyte counts was driven by an increase in the number of lymphocytes (P<0.001) and, to a minor extent, monocytes (P<0.01).This study shows that reduced systemic inflammation and increased reverse cholesterol transport together drive macrophage ABCA1-mediated protection against atherosclerosis. Show less
Calpe-Berdiel, L.; Zhao, Y.; Graauw, M. de; Ye, D.; Santbrink, P.J. van; Mommaas, A.M.; ... ; Berkel, T.J.C. van 2012
OBJECTIVE The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been... Show moreOBJECTIVE The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been suggested that ABCA2 sequesters cholesterol inside the lysosomes, however, little is known of the macrophage-specific role of ABCA2 in regulating lipid homeostasis in vivo and in modulating susceptibility to atherosclerosis. METHODS Chimeras with dysfunctional macrophage ABCA2 were generated by transplantation of bone marrow from ABCA2 knockout (KO) mice into irradiated LDL receptor (LDLr) KO mice. RESULTS Interestingly, lack of ABCA2 in macrophages resulted in a diminished lesion size in the aortic root (-24.5%) and descending thoracic aorta (-36.6%) associated with a 3-fold increase in apoptotic cells, as measured by both caspase 3 and TUNEL. Upon oxidized LDL exposure, macrophages from wildtype (WT) transplanted animals developed filipin-positive droplets in lysosomal-like compartments, corresponding to free cholesterol (FC) accumulation. In contrast, ABCA2-deficient macrophages displayed an abnormal diffuse distribution of FC over peripheral regions. The accumulation of neutral sterols in lipid droplets was increased in ABCA2-deficient macrophages, but primarily in cytoplasmic clusters and not in lysosomes. Importantly, apoptosis of oxLDL loaded macrophages lacking ABCA2 was increased 2.7-fold, probably as a consequence of the broad cellular distribution of FC. CONCLUSIONS Lack of functional ABCA2 generates abnormalities in intracellular lipid distribution/trafficking in macrophages consistent with its lysosomal sequestering role, leading to an increased susceptibility to apoptosis in response to oxidized lipids and reduced atherosclerotic lesion development. Show less
Calpe-Berdiel, L.; Zhao, Y.; Graauw, M. de; Ye, D.; Santbrink, P.J. van; Mommaas, A.M.; ... ; Berkel, T.J.C. van 2012
ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies... Show moreABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen. Show less
