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Impact of bone marrow ATP-binding cassette transporter A1 deficiency on atherogenesis is independent of the presence of the low-density lipoprotein receptor
Ouweneel, A.B.; Zhao, Y.; Calpe-Berdiel, L.; Lammers, B.; Hoekstra, M.; Berkel, T.J.C. van; Eck, M. van 2021
Impact of bone marrow ATP-binding cassette transporter A1 deficiency on atherogenesis is independent of the presence of the low-density lipoprotein receptor
Article / Letter to editor
open access
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
Disruption of phospholipid transfer protein-mediated high-density lipoprotein maturation reduces scavenger receptor BI deficiency-driven atherosclerosis susceptibility despite unexpected metabolic complications
Hoekstra, M.; Sluis, R.J. van der; Hildebrand, R.B.; Lammers, B.; Zhao, Y.; Pratico, D.; ... ; Eck, M. van 2020
Disruption of phospholipid transfer protein-mediated high-density lipoprotein maturation reduces scavenger receptor BI deficiency-driven atherosclerosis susceptibility despite unexpected metabolic complications
Article / Letter to editor
open access
Objective:We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger... Show moreObjective:We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice.Approach and Results:We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BIxPLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was-however-only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet-fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [C-14]cholesteryl oleate after intravenous VLDL-like particle injection.Conclusions:We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice. Show less
Disruption of PLTP (phospholipid transfer protein)-mediated HDL (high-density lipoprotein) maturation reduces SR-BI (scavenger receptor BI) deficiency-driven atherosclerosis susceptibility despite unexpected metabolic complications
Hoekstra, M.; Sluis, R.J. van der; Hildebrand, R.B.; Lammers, B.; Zhao, Y.; Praticò, D.; ... ; Eck, M. van 2020
Disruption of PLTP (phospholipid transfer protein)-mediated HDL (high-density lipoprotein) maturation reduces SR-BI (scavenger receptor BI) deficiency-driven atherosclerosis susceptibility despite unexpected metabolic complications
Article / Letter to editor
open access
2020-07-17T00:00:00Z
C]cholesteryl oleate after intravenous VLDL-like particle injection.\nWe have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in... Show moreC]cholesteryl oleate after intravenous VLDL-like particle injection.\nWe have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.\nOBJECTIVE\nCONCLUSIONS Show less
Abca1 deficiency protects the heart against myocardial infarction-induced injury
Louwe, M.C.; Lammers, B.; Frias, M.A.; Foks, A.C.; Leeuw, L.R. de; Hildebrand, R.B.; ... ; Eck, M. van 2016
Abca1 deficiency protects the heart against myocardial infarction-induced injury
Article / Letter to editor
metadata only
Conclusions: Although Abca1 has a protective role in atherosclerosis, it exerts detrimental effects on cardiac function after MI. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an... Show moreConclusions: Although Abca1 has a protective role in atherosclerosis, it exerts detrimental effects on cardiac function after MI. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
ABCA1 deficiency protects the heart against myocardial infarction-induced injury
Louwe, M.C.; Lammers, B.; Frias, M.A.; Foks, A.C.; Leeuw, L.R. de.; Hildebrand, R.B.; ... ; Eck, M. van 2016
ABCA1 deficiency protects the heart against myocardial infarction-induced injury
Article / Letter to editor
open access
Background and aims We explored the role of ATP-binding cassette transporter A1 (Abca1), in post-myocardial infarction (MI) cardiac injury. Methods In Abca1–/– mice, wild type (WT) mice, and WT... Show more

Background and aims We explored the role of ATP-binding cassette transporter A1 (Abca1), in post-myocardial infarction (MI) cardiac injury. Methods In Abca1–/– mice, wild type (WT) mice, and WT mice transplanted with Abca1–/– or WT bone marrow, an MI was induced in vivo. Furthermore, an ex vivo MI was induced in isolated Abca1–/– and WT hearts. Results Twenty-four hours and two weeks after in vivo MI induction, MI size was reduced in Abca1–/– (−58%, p = 0.007; −59%, p = 0.03) compared to WT. Ex vivo MI induction showed no effect of Abca1–/– on infarct size. Interestingly, two weeks after MI, Abca1–/– mice showed higher circulating levels of B-cells (+3.0 fold, p = 0.02) and T-cells (+4.2 fold, p = 0.002) compared to WT. Bone marrow-specific Abca1–/– tended to reduce infarct size (−43%, p = 0.12), suggesting a detrimental role for hematopoietic Abca1 after MI. Conclusions Although Abca1 has a protective role in atherosclerosis, it exerts detrimental effects on cardiac function after MI. Keywords

  • Abca1 deficiency;
  • Myocardial infarction;
  • Immune cells;
  • Mice

Show less
Abca1 deficiency protects the heart against myocardial infarction-induced injury
Louwe, M.C.; Lammers, B.; Frias, M.A.; Foks, A.C.; Leeuw, L.R. de; Hildebrand, R.B.; ... ; Eck, M. van 2016
Abca1 deficiency protects the heart against myocardial infarction-induced injury
Article / Letter to editor
open access
Background and aims We explored the role of ATP-binding cassette transporter A1 (Abca1), in post-myocardial infarction (MI) cardiac injury. Methods In Abca1–/– mice, wild type (WT) mice, and WT... Show moreBackground and aims We explored the role of ATP-binding cassette transporter A1 (Abca1), in post-myocardial infarction (MI) cardiac injury. Methods In Abca1–/– mice, wild type (WT) mice, and WT mice transplanted with Abca1–/– or WT bone marrow, an MI was induced in vivo. Furthermore, an ex vivo MI was induced in isolated Abca1–/– and WT hearts. Results Twenty-four hours and two weeks after in vivo MI induction, MI size was reduced in Abca1–/– (−58%, p = 0.007; −59%, p = 0.03) compared to WT. Ex vivo MI induction showed no effect of Abca1–/– on infarct size. Interestingly, two weeks after MI, Abca1–/– mice showed higher circulating levels of B-cells (+3.0 fold, p = 0.02) and T-cells (+4.2 fold, p = 0.002) compared to WT. Bone marrow-specific Abca1–/– tended to reduce infarct size (−43%, p = 0.12), suggesting a detrimental role for hematopoietic Abca1 after MI. Conclusions Although Abca1 has a protective role in atherosclerosis, it exerts detrimental effects on cardiac function after MI. Keywords * Abca1 deficiency; * Myocardial infarction; * Immune cells; * Mice Show less
Hematopoietic alpha 7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis
Kooijman, S.; Meurs, I.; Stoep, M. van der; Habets, K.L.; Lammers, B.; Berbee, J.F.P.; ... ; Rensen, P.C.N. 2015
Hematopoietic alpha 7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis
Article / Letter to editor
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Hematopoietic alpha 7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis
Kooijman, S.; Meurs, I.; Van der Stoep, M.; Habets, K.L.; Lammers, B.; Berbee, J.F.P.; ... ; Rensen, P.C.N. 2015
Hematopoietic alpha 7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis
Article / Letter to editor
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Orp8 Deficiency in Bone Marrow-Derived Cells Reduces Atherosclerotic Lesion Progression in LDL Receptor Knockout Mice
Kampen, E. van; Beaslas, O.; Hildebrand, R.B.; Lammers, B.; Berkel, T.J.C. van; Olkkonen, V.M.; Eck, M. van 2014
Orp8 Deficiency in Bone Marrow-Derived Cells Reduces Atherosclerotic Lesion Progression in LDL Receptor Knockout Mice
Article / Letter to editor
open access
Leukocyte ABCA1 remains atheroprotective in splenectomized LDL receptor knockout mice
Lammers, B.; Zhao, Y.; Foks, A.C.; Hildebrand, R.B.; Kuiper, J.; Berkel, T.J. van; Eck, M. van 2012
Leukocyte ABCA1 remains atheroprotective in splenectomized LDL receptor knockout mice
Article / Letter to editor
open access
Human ATP-Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation
Olivier, M.; Tanck, M.W.; Out, R.; Villard, E.F.; Lammers, B.; Bouchareychas, L.; ... ; Goff, W. le 2012
Human ATP-Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation
Article / Letter to editor
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Macrophage lipid genes in cardiovascular disease
Lammers, B. 2012
Macrophage lipid genes in cardiovascular disease
Doctoral Thesis
open access
2014-09-12T00:00:00Z; 2012-09-12T00:00:00Z; 2012-09-12T00:00:00Z; 2012-09-12T00:00:00Z; 2014-09-12T00:00:00Z; 2012-09-12T00:00:00Z; 2014-09-12T00:00:00Z; 2014-09-12T00:00:00Z; 2014-09-12T00:00:00Z; 2014-03-12T00:00:00Z; 2014-03-12T00:00:00Z; 2012-09-12T00:00:00Z; 2012-09-12T00:00:00Z; 2012-09-12T00:00:00Z; 2012-09-12T00:00:00Z
In dit proefschrift wordt onderzoek beschreven waarin een aantal door lipiden gereguleerde genen op bepaalde witte bloedcellen (macrofagen) zijn onderzocht voor nieuwe behandelmethoden ter... Show moreIn dit proefschrift wordt onderzoek beschreven waarin een aantal door lipiden gereguleerde genen op bepaalde witte bloedcellen (macrofagen) zijn onderzocht voor nieuwe behandelmethoden ter voorkoming of behandeling van atherosclerose (slagaderverkalking). Dit wordt gedaan met behulp van de beenmergtransplantatie techniek, waarmee specifiek witte bloedcellen __ waaronder ook macrofagen __ worden vervangen. De in het proefschrift beschreven genen die met behulp van de beenmergtransplantatietechniek zijn onderzocht zijn: ATP-binding cassette transporter (ABC)A1, ABCG1, apolipoproteine (apo)E, en adipose triglyceride lipase (ATGL). Deze genen worden gereguleerd door lipiden en spelen een belangrijke rol in de lipiden homeostase van cellen. Allereerst bleek dat ABCA1 en apoE in macrofagen op verschillende wijze een beschermende werking hebben met betrekking tot atherosclerose, en dat ze gezamenlijk ontstekingsremmend werken. In overeenstemming met deze resultaten bleken ABCG1 en apoE in macrofagen geheel onafhankelijk van elkaar een beschermende rol te spelen in de ontwikkeling van atherosclerose. Afwezigheid van ATGL __ verantwoordelijk voor de afbraak van vetten - in macrofagen leidde verrassenderwijs tot een vermindering van atherosclerose. De afwezigheid van ABCA1 bleek te beschermen tegen een acute hartaanval. Daarnaast bleek dat macrofaag ABCA1 veranderingen in de milt teweegbrengt, maar dat dit geen gevolgen heeft voor de ontwikkeling van atherosclerose. Show less
The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis
Meurs, I.; Lammers, B.; Zhao, Y.; Out, R.; Hildebrand, R.B.; Hoekstra, M.; ... ; Eck, M. van 2012
The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis
Article / Letter to editor
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The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis
Meurs, I.; Lammers, B.; Zhao, Y.; Out, R.; Hildebrand, R.B.; Hoekstra, M.; ... ; Eck, M. van 2012
The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis
Article / Letter to editor
open access
Augmented atherogenesis in LDL receptor deficient mice lacking both macrophage ABCA1and ApoE
Lammers, B.; Zhao, Y.; Hoekstra, M.; Hildebrand, R.B.; Ye, D.; Meurs, I.; ... ; Eck, M. van 2011
Augmented atherogenesis in LDL receptor deficient mice lacking both macrophage ABCA1and ApoE
Article / Letter to editor
open access
Aim 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,... Show moreAim 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. Methods and ResultsLDL 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±94×103 µm2), however, was 1.9-fold (p<0.01) and 1.6-fold (p<0.01) increased compared to single knockouts (ABCA1 KO: 341±20×103 µm2; apoE KO: 402±78×103 µm2, respectively) and 3.1-fold increased (p<0.001) compared to WT (211±20×103 µm2). 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. Show less
Restoration of High-Density Lipoprotein Levels by Cholesteryl Ester Transfer Protein Expression in Scavenger Receptor Class B Type I (SR-BI) Knockout Mice Does Not Normalize Pathologies Associated With SR-BI Deficiency
Hildebrand, R.B.; Lammers, B.; Meurs, I.; Korporaal, S.J.A.; Haan, W. de; Zhao, Y.; ... ; Eck, M. van 2010
Restoration of High-Density Lipoprotein Levels by Cholesteryl Ester Transfer Protein Expression in Scavenger Receptor Class B Type I (SR-BI) Knockout Mice Does Not Normalize Pathologies Associated With SR-BI Deficiency
Article / Letter to editor
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Objective-Disruption of scavenger receptor class B type I (SR-BI) in mice impairs high-density lipoprotein (HDL)-cholesterol (HDL-C) delivery to the liver and induces susceptibility to... Show moreObjective-Disruption of scavenger receptor class B type I (SR-BI) in mice impairs high-density lipoprotein (HDL)-cholesterol (HDL-C) delivery to the liver and induces susceptibility to atherosclerosis. In this study, it was investigated whether introduction of cholesteryl ester transfer protein (CETP) can normalize HDL-C transport to the liver and reduce atherosclerosis in SR-BI knockout (KO) mice. Methods and Results-Expression of human CETP in SR-BIKO mice resulted in decreased plasma HDL-C levels, both on chow diet (1.8-fold, P < 0.001) and on challenge with Western-type diet (1.6-fold, P < 0.01). Furthermore, the presence of CETP partially normalized the abnormally large HDL particles observed in SR-BIKO mice. Unexpectedly, expression of CETP in SR-BIKO mice did not reduce atherosclerotic lesion development, probably because of consequences of SR-BI deficiency, including the persistence of higher VLDL-cholesterol (VLDL-C) levels, unchanged elevated free cholesterol/total cholesterol ratio, and the increased oxidative status of the animals. In addition, CETP expression did not normalize other characteristics of SR-BI deficiency, including female infertility, reticulocytosis, thrombocytopenia, and impaired platelet aggregation. Conclusion-CETP restores HDL-C levels in SR-BIKO mice, but it does not change the susceptibility to atherosclerosis and other typical characteristics that are associated with SR-BI disruption. This may indicate that the pathophysiology of SR-BI deficiency is not a direct consequence of changes in the HDL pool. (Arterioscler Thromb Vasc Biol. 2010; 30: 1439-1445.) Show less
Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production
Hoekstra, M.; Ye, D.; Hildebrand, R.B.; Zhao, Y.; Lammers, B.; Stitzinger, M.; ... ; Eck, M. van 2009
Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production
Article / Letter to editor
open access
2011-01-01T00:00:00Z