Accelerated atherosclerosis in C57Bl/6 mice transplanted with ApoE-deficient bone marrow

Eck, Miranda Van; Herijgers, N.; Vidgeon-Hart, Martin; Pearce, Nigel J.; Hoogerbrugge, Peter M.; Groot, P.H.E.; Berkel, Theo J.C. Van

doi:10.1016/s0021-9150(99)00372-x

Cited by 44 publications

(41 citation statements)

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“…We showed that low level expression of apoE secretion by arterial macrophages in apoE-deficient mice delays atherogenesis (24). In addition, we and others demonstrated that lack of apoE expression by the macrophage promotes foam cell formation in wild-type mice (5,6), supporting a protective role for apoE expression by the macrophage in the early stage of atherogenesis. The present study confirms these observations by showing that the mean lesion area in aortic cross-sections was increased by 85% in mice reconstituted with apoE Ϫ/Ϫ MFG compared with apoE ϩ/ϩ MFG mice, in the absence of differences in plasma lipid lipoprotein levels or apoE expression in serum.…”

Section: Discussionsupporting

confidence: 52%

“…In support of this hypothesis, Brown and Goldstein (4) have shown that macrophage-derived foam cells release an excess of free cholesterol associated with apoE within HDL particles (4). In addition, we and others (5,6) previously provided in vivo evidence that the lack of apoE expression by macrophages promotes foam cell formation. These data support a protective role for apoE expression by the macrophage in the early stages of atherogenesis.…”

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confidence: 54%

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Retrovirus-mediated Expression of Apolipoprotein A-I in the Macrophage Protects against Atherosclerosis in Vivo

Ishiguro

Yoshida²,

Major

et al. 2001

Journal of Biological Chemistry

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We have previously reported that the lack of apolipoprotein (apo) E expression by macrophages promotes foam cell formation in vivo. Because transgenic mice overexpressing human apoA-I from the liver (h-apoA-I TgN) are protected from the atherogenesis induced by apoE deficiency, we hypothesized that the presence of apoA-I in the vessel wall could reduce the negative effect of apoE deficiency on lesion growth. To address this issue, we used both retroviral transduction and transgenic approaches to produce in vivo systems where apoA-I is expressed from macrophages. In the retroviral transduction study, apoA-I-deficient (apoA-I ؊/؊ ) mice reconstituted with apoE-deficient (apoE ؊/؊ ) bone marrow cells that were infected with a retroviral vector expressing human apoA-I (MFG-HAI) had 95% lower atherosclerotic lesion area than that of recipients of apoE ؊/؊ bone marrow cells infected with the parental virus (MFG). To determine whether the protective effect of locally produced apoA-I was due to the lack of systemic apoA-I, we conducted a different experiment using h-apoA-I TgN mice as recipients of apoE ؊/؊ bone marrow with or without human apoA-I (driven by a macrophage-specific transgene defined as m-AI). Aortic lesion area in apoE ؊/؊ /m-AI 3 h-apoA-I TgN mice was decreased by 85% compared with apoE ؊/؊ 3 h-apoA-I TgN mice. These data demonstrate that expression of apoA-I from macrophages protects against atherogenesis without affecting plasma apoA-I and high density lipoprotein cholesterol levels.

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Section: Discussionsupporting

confidence: 52%

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confidence: 54%

Retrovirus-mediated Expression of Apolipoprotein A-I in the Macrophage Protects against Atherosclerosis in Vivo

Ishiguro

Yoshida²,

Major

et al. 2001

Journal of Biological Chemistry

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“…Strong support of a direct effect of apoE in the artery wall comes from bone marrow transplantation studies (1,2). We have reported that the lack of macrophage apoE in C57BL/6 mice increases the size of diet-induced arterial lesions by 10-fold in the absence of differences in plasma lipoprotein levels (3).…”

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confidence: 95%

Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice

Fazio

Babaev

Burleigh³

et al. 2002

Journal of Lipid Research

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We have previously reported that the introduction of macrophage apoE into mice lacking both apoE and the LDL receptor (apoE ؊ / ؊ /LDLR ؊ / ؊ ) through bone marrow transplantation (apoE ؉ / ؉ /LDLR ؊ / ؊ → apoE ؊ / ؊ /LDLR ؊ / ؊ ) produces progressive accumulation of apoE in plasma without affecting lipid levels. This model provides a tool to study the effects of physiologically regulated amounts of macrophage apoE on atherogenesis in hyperlipidemic animals. Ten-week-old male apoE ؊ / ؊ /LDLR ؊ / ؊ mice were transplanted with either apoE ؉ / ؉ /LDLR ؊ / ؊ (n ‫؍‬ 11) or apoE ؊ / ؊ / LDLR ؊ / ؊ (n ‫؍‬ 14) marrow. Although there were no differences between the two groups in lipid levels at baseline or at 5 and 9 weeks after transplantation, apoE levels in the apoE ؉ / ؉ LDLR ؊ / ؊ → apoE ؊ / ؊ /LDLR ؊ / ؊ mice increased to 4 times the apoE levels of normal mice. This resulted in a 60% decrease in aortic atherosclerosis in the apoE Although apolipoprotein E (apoE) of macrophage origin is fully functional in its ability to induce the clearance of plasma lipoproteins, substantial evidence supports the concept of a direct anti-atherogenic effect of apoE in the arterial wall. Strong support of a direct effect of apoE in the artery wall comes from bone marrow transplantation studies (1, 2). We have reported that the lack of macrophage apoE in C57BL/6 mice increases the size of diet-induced arterial lesions by 10-fold in the absence of differences in plasma lipoprotein levels (3). We have also shown that apoE Ϫ / Ϫ macrophages increase lesion size in apoA-I deficient and apoA-I over-expressing mice (4). In addition, using a retroviral transduction system, we have shown that low level expression of apoE from macrophages has a strong anti-atherogenic effect during foam cell lesion formation, but this effect was lost when the plaques grew larger and more complex, an indication that the protective capacity of apoE is eventually overwhelmed by the severe hyperlipidemia of apoE deficiency (5). Evidence in favor of an anti-atherogenic role of apoE also comes from studies showing that low level expression of human apoE-3 in the arterial wall of apoE Ϫ / Ϫ mice was accompanied by decreased growth of lesions without affecting plasma lipids (6), and that the expression of low levels of human apoE-3 in the macrophages of apoE Ϫ / Ϫ mice resulted in decreased atherogenesis independent of a decrease in plasma cholesterol (7). Interestingly, recent studies from our laboratory have shown that retroviral transfer of receptor-binding defective mutant forms of human apoE, such as apoE-2 and apoE-cys142, do not protect apoE null mice against atherosclerosis development, suggesting that the local function of apoE is linked to its ability to bind receptors Abbreviations: BMT, bone marrow transplant; HSPG, heparan sulfate proteoglycans; LDLR, low density lipoprotein receptor; LXR, liver X receptor; TNF ␣ , tumor necrosis factor ␣ .

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“…24,25 Macrophages synthesize and secrete apoE, which makes contribution to the apoE pool in the blood circulation and associates with plasma lipoproteins and accelerates their clearance in vivo. 26,27 Macrophage-derived apoE can also act as a cholesterol acceptor to Original …”

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confidence: 99%

Macrophage Phospholipid Transfer Protein Deficiency and ApoE Secretion

Liu

Hojjati

Devlin

et al. 2007

ATVB

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Objective-PLTP and apoE play important roles in lipoprotein metabolism and atherosclerosis. It is known that formation of macrophage-derived foam cells (which highly express PLTP and apoE) is the critical step in the process of atherosclerosis. We investigated the relationship between PLTP and apoE in macrophages and the atherogenic relevance in a mouse model. Methods and Results-We transplanted PLTP-deficient mouse bone marrow into apoE-deficient mice (PLTP Key Words: phospholipid transfer protein Ⅲ apoE Ⅲ bone marrow transplantation Ⅲ macrophage Ⅲ lipoprotein Ⅲ atherosclerosis P lasma PLTP is known to be an independent risk factor for coronary artery disease, 1 and is significantly increased in obesity, as well as in diabetes. 2,3 Moreover, PLTP deficiency decreases, 4 and PLTP overexpression increases, 5,6 atherosclerosis in mouse models, so that it is considered a potential target for pharmacological or gene therapy. However, research toward this goal is hampered by the fact that the mechanism of the atherogenicity of PLTP is not completely understood. This is a multifunctional protein that is expressed in a variety of tissues, with some of its effects considered proatherogenic, 7,8 and others antiatherogenic. 9 -11 ApoE is a multifunctional protein that is synthesized by the liver and several peripheral tissues and cell types. 12,13 ApoE serves as a ligand for receptor-mediated uptake of lipoproteins through the LDL receptor, the LDL receptor-related protein, and heparan sulfate proteoglycans. 14 ApoE also plays a key role in intracellular lipid metabolism, influencing processes such as the assembly and secretion of lipoproteins 15,16 and cholesterol efflux to HDL. 17 The relationship between PLTP and apoE is mostly unknown. In type 2 diabetes, PLTP activity was positively correlated with plasma apoE levels. 18 Of the circulating PLTP mass only a minor portion is in the active form in normolipidemic subjects. 19 It has been reported that active PLTP in plasma is associated with apoE but not with apoA-I, 20 and apoE proteoliposomes can convert inactive PLTP into active one. 21 There is a hypothesis that transfer of active PLTP from apoE-containing lipoproteins to apoA-I-containing ones results in the conversion of active PLTP to inactive PLTP. 20 However, this is not confirmed by a recent report, indicating that active plasma PLTP is associated primarily with apoA-I but not apoE-containing lipoproteins. 22 The formation of foam cells from lipid-accumulated macrophages is a critical step in atherogenesis. Both macrophages and macrophage-derived foam cells express PLTP. 23 It has recently been shown that PLTP is highly expressed in macrophages from atherosclerotic lesions. 24,25 Macrophages synthesize and secrete apoE, which makes contribution to the apoE pool in the blood circulation and associates with plasma lipoproteins and accelerates their clearance in vivo. 26,27 Macrophage-derived apoE can also act as a cholesterol acceptor to Original

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Accelerated atherosclerosis in C57Bl/6 mice transplanted with ApoE-deficient bone marrow

Cited by 44 publications

References 45 publications

Retrovirus-mediated Expression of Apolipoprotein A-I in the Macrophage Protects against Atherosclerosis in Vivo

Retrovirus-mediated Expression of Apolipoprotein A-I in the Macrophage Protects against Atherosclerosis in Vivo

Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice

Macrophage Phospholipid Transfer Protein Deficiency and ApoE Secretion

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