ApoA1 Reduces Free Cholesterol Accumulation in Atherosclerotic Lesions of ApoE–Deficient Mice Transplanted With ApoE–Expressing Macrophages

Boisvert, William A.; Black, Audrey S.; Curtiss, Linda K.

doi:10.1161/01.atv.19.3.525

Cited by 58 publications

(52 citation statements)

References 46 publications

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“…In another study, mice deficient in both apoE and apoA-I but expressing macrophage-derived apoE were found to have 2-to 3-fold lower plasma cholesterol than mice deficient in only apoE and expressing macrophage apoE. In spite of the lower plasma cholesterol, the apoA-I and apoE double knockout mice had atherosclerotic lesions 60% larger than in the apoE only knockout mice expressing macrophage apoE (9). More recently, using a method of monitoring the in vivo fate of radiolabeled macrophage cholesterol, a study showed that overexpression of liver-derived apoA-I promotes reverse cholesterol transport from macrophages to feces more efficiently than in mice with normal levels of plasma apoA-I (10).…”

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confidence: 97%

Inflammation and skin cholesterol in LDLr−/−, apoA-I−/− mice: link between cholesterol homeostasis and self-tolerance?

Zabalawi

Bharadwaj

Horton

et al. 2007

Journal of Lipid Research

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confidence: 97%

Inflammation and skin cholesterol in LDLr−/−, apoA-I−/− mice: link between cholesterol homeostasis and self-tolerance?

Zabalawi

Bharadwaj

Horton

et al. 2007

Journal of Lipid Research

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“…ApoE is also an acceptor for FC and phospholipid released from macrophages by ABCA1 (7). Additionally, apoE has been reported to stimulate cholesterol release from macrophages to apoA-I-containing acceptors (8)(9)(10). ApoE also enhances HDL or apoA-I interaction with vascular wall cells and extracellular matrix (11), activities that could contribute to the atheroprotection due to low-level apoE expression.…”

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confidence: 99%

Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression

Thorngate

Yancey

Kellner-Weibel

et al. 2003

Journal of Lipid Research

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Low levels of transgenic mouse apolipoprotein E (apoE) suppress atherosclerosis in apoE knockout (apoE ؊ / ؊ ) mice without normalizing plasma cholesterol. To test whether this is due to facilitation of cholesterol efflux from the vessel wall, we produced apoA-I ؊ / ؊ /apoE ؊ / ؊ mice with or without the transgene. Even without apoA-I and HDL, apoA-I ؊ / ؊ /apoE ؊ / ؊ mice had the same amount of aorta cholesteryl ester as apoE ؊ / ؊ mice. Low apoE in the apoA-I ؊ / ؊ / apoE ؊ / ؊ transgenic mice reduced aortic lesions by 70% versus their apoA-I ؊ / ؊ /apoE ؊ / ؊ siblings. To define the free cholesterol (FC) efflux capacity of lipoproteins from the various genotypes, sera were assayed on macrophages expressing ATP-binding cassette transporter A1 (ABCA1). Surprisingly, ABCA1 FC efflux was twice as high to sera from the apoA-I ؊ / ؊ /apoE ؊ / ؊ or apoE ؊ / ؊ mice compared with wildtype mice, and this activity correlated with serum apoA-IV. Immunodepletion of apoA-IV from apoA-I ؊ / ؊ /apoE ؊ / ؊ serum abolished ABCA1 FC efflux, indicating that apoAI-V serves as a potent acceptor for FC efflux via ABCA1. With increasing apoE expression, apoA-IV and FC acceptor capacity decreased, indicating a reciprocal relationship between plasma apoE and apoA-IV.Low plasma apoE (1-3 ؋ 10 ؊ 8 M) suppresses atherosclerosis by as yet undefined mechanisms, not dependent on the presence of apoA-I or HDL or an increased capacity of serum acceptors for FC efflux. The prevention of atherosclerosis by apolipoprotein E (apoE) is generally attributed to the removal of plasma lipoprotein remnant particles; however, previous studies by our group suggest that apoE may have a role in preventing atherosclerosis in addition to its role in remnant clearance. In transgenic apoE-knockout (apoE Ϫ / Ϫ ) mice making mouse apoE specifically in the adrenal gland, we unexpectedly found that atherosclerosis was reduced by 80-95% in two transgenic lines expressing insufficient amounts of apoE to correct their hypercholesterolemia. This protection persists over the life of these animals, up to almost 2 years, with no detectable differences from apoE Ϫ / Ϫ siblings in their total plasma cholesterol or remnant lipoproteins (2).Several groups have demonstrated that apoE expressed by macrophages in apoE Ϫ / Ϫ mice at levels too low to correct hypercholesterolemia significantly reduces atherosclerosis (3, 4). They suggest this protection is due to apoE production by macrophages in the arterial wall leading to increased efflux of cholesterol from arterial macrophages and thereby inhibiting foam cell development. The initial step in reverse cholesterol transport is hypothesized to be the release of free cholesterol (FC) and phospholipid from the plasma membrane of cells to acceptor particles such as HDL or lipid-poor apolipoproteins. Lipid-poor apoA-I stimulates release of cholesterol and phospholipid from macrophages via the ATP-binding cassette transporter A1 (ABCA1) (5, 6). ApoE is also an acceptor for FC and phospholipid released from macrophages by ABC...

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“…94059, Harlan Teklad). 4 The mice were housed 4 per cage in autoclaved filter-topped cages with autoclaved water and kept on a 12-hour light-dark cycle. All procedures were performed in accordance with institutional guidelines.…”

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Effect of γ-Irradiation and Bone Marrow Transplantation on Atherosclerosis in LDL Receptor-Deficient Mice

Schiller

Kubo

Boisvert

et al. 2001

ATVB

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Abstract-Bone marrow transplantation (BMT) is commonly used to study the participation of bone marrow-derived cells in atherosclerosis. To determine the effect of this methodology on lesions, 16 male low density lipoprotein (LDL) receptor knockout (LDLrϪ/Ϫ) mice were reconstituted with bone marrow from syngeneic LDLrϪ/Ϫ mice after 10 Gy ␥-irradiation and compared with 12 male LDLrϪ/Ϫ littermates that did not undergo BMT (no-BMT group). Mice were fed a high fat diet (HFD) for 16 weeks to induce atherosclerosis. Sixteen additional LDLrϪ/Ϫ mice underwent BMT, and 12 male LDLrϪ/Ϫ mice that did not undergo BMT were fed a chow diet for 56 weeks. Thoracic aorta lesion areas were smaller in BMT mice than in no-BMT mice fed the HFD (PϽ0.0001). In contrast, aortic root lesion areas were greater in the BMT mice fed the HFD (PϽ0.0001) as well as in those fed the chow diet (Pϭ0.0001). Abdominal aorta free cholesterol and cholesteryl ester mass were minimal in all groups studied. Aortic root lesions from all no-BMT mice were densely collagenous and encapsulated by a cellular cap, whereas lesions in the BMT mice contained lipid cores and minimal collagen staining. Although the reason for these differences in lesion size and composition remains unresolved, this study suggests that multiple parameters of lesion formation should be examined to assess atherosclerosis. Key Words: bone marrow transplantation Ⅲ ␥-radiation Ⅲ macrophages Ⅲ collagen Ⅲ hyperlipidemia T he LDL receptor knockout (LDLrϪ/Ϫ) mouse is a particularly suitable model for studying atherosclerosis. These mice develop atherosclerotic lesions predominantly in the aortic sinus when they are fed a chow diet, whereas they develop extensive lesions throughout the aortic root and the length of the entire aorta when they are fed a high fat diet (HFD). 1 Atherosclerosis in mice has been assessed by crosssectional analysis of the aortic sinus, 2 and morphometric methods are also available to quantify the extent of lesion involvement in the entire aortic tree by measuring stained en face dissected aortas. 3 More recently, free cholesterol and cholesteryl ester mass measurements of dissected, homogenized, and lipid-extracted aortas have been used to assess atherosclerosis. 4 Lethal total body ␥-irradiation of atherosclerosis-prone mice followed by bone marrow reconstitution from donors with transgenic alterations in the innate and acquired immune systems has been used experimentally to identify the role of bone marrow-derived cells in atherosclerosis. 5 Although in all cases the experimental mice are compared with control mice that have undergone comparable irradiation and reconstitution with syngeneic wild-type bone marrow, the direct effects of lethal total body irradiation and syngeneic bone marrow transplantation (BMT) on atherosclerosis have not been examined. In this methodological study, we examined the effects of this experimental model on atherosclerosis in male LDLrϪ/Ϫ mice fed either an HFD for 16 weeks to induce rapid lesion formation or a chow diet for 56 weeks t...

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ApoA1 Reduces Free Cholesterol Accumulation in Atherosclerotic Lesions of ApoE–Deficient Mice Transplanted With ApoE–Expressing Macrophages

Cited by 58 publications

References 46 publications

Inflammation and skin cholesterol in LDLr−/−, apoA-I−/− mice: link between cholesterol homeostasis and self-tolerance?

Inflammation and skin cholesterol in LDLr−/−, apoA-I−/− mice: link between cholesterol homeostasis and self-tolerance?

Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression

Effect of γ-Irradiation and Bone Marrow Transplantation on Atherosclerosis in LDL Receptor-Deficient Mice

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