Inhibition of Atherosclerosis Development in Cholesterol-Fed Human Apolipoprotein A-I–Transgenic Rabbits

Duverger, Nicolas; Kruth, Howard S.; Emmanuel, Florence; Caillaud, Jean‐Michel; Viglietta, C.; Castro, Graciela; Tailleux, Anne; Fiévet, Catherine; Fruchart, Jean Charles; Houdebine, Louis; Denèfle, Patrice

doi:10.1161/01.cir.94.4.713

Cited by 209 publications

(120 citation statements)

References 33 publications

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“…One mechanism by which apoA-I and HDL may act to prevent atherosclerosis progression in this model is the enhancement of cholesterol efflux. In vitro studies confirmed that cholesterol efflux is increased when Fu5AH hepatoma cells are incubated with sera from apoA-I transgenic versus control rabbits (17). Paszty et al and others (20,19) introduced the human apoA-I transgene into the hypercholesterolemic apoE knockout background to examine if increases in apoA-I and HDL cholesterol levels are also effective in minimizing the harmful effect of apoE deficiency.…”

Section: Discussionmentioning

confidence: 91%

“…ABCA1 knockout mice have greatly reduced HDL cholesterol and apoA-I levels, and accumulation of foam cells in tissues. Substantial support for the concept that overexpression of human apoA-I reduces atherogenesis has been provided in studies utilizing rabbits fed a high fat diet (17), as well as transgenic C57BL/6 and hyperlipidemic mice (18 -20). These studies show that increased levels of human apoA-I in plasma effectively delay the progression of atherosclerosis.…”

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confidence: 99%

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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: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

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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“…[31][32][33] When high levels of human apoA1 are expressed in transgenic mice, there is significant inhibition of fatty streak lesion formation, 34 and the overexpression of human apoA1 in apoE-deficient mice results in a dramatic reduction in atherosclerosis. 35,36 Similarly, atherosclerosis is reduced in cholesterol-fed transgenic rabbits that express human apoA1, 37 and a deficiency of apoA1 can exacerbate atherosclerosis in human apoB-transgenic mice. 38 Although "lesion" apoA1 was not measured in any of these other studies, it is reasonable to assume that higher plasma HDL levels would facilitate higher HDL penetration into the aortic wall, which could in turn lead to enhanced cholesterol removal from lesions.…”

Section: Discussionmentioning

confidence: 99%

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

Boisvert

Black

Curtiss

1999

ATVB

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Abstract-Along with apolipoprotein (apo) E, which promotes cholesterol efflux from foam cells, apoA1-containing high density lipoprotein (HDL) is thought to facilitate the transport of cholesterol from lesions. This role for apoA1 was tested in vivo by lethally irradiating apoE-deficient and apoE-plus apoA1-deficient mice and reconstituting them with bone marrow cells isolated from wild-type (WT) mice. ApoE, but not apoA1, was synthesized by the transplanted bone marrow-derived cells. Therefore, this transplantation procedure generated apoE-deficient animals with atherosclerotic lesions that contained both apoE and apoA1 (E/A1 mice) and apoE-deficient animals with lesions that contained apoE but no apoA1 (E/A1o mice). As shown previously, the transplanted WT macrophage-derived apoE dramatically lowered the plasma hypercholesterolemia in both groups. On feeding with an atherogenic diet after transplantation, plasma cholesterol levels were raised in both groups of mice, but the levels in the E/A1 mice at 20 weeks were 2-to 3-fold higher than in E/A1o mice. Immunohistochemical staining verified that apoE was abundant in lesions of both groups, whereas apoA1 was detected in the lesions of E/A1 mice only. Despite a 2-to 3-fold lower total plasma cholesterol in the E/A1o mice, the free cholesterol recovered from isolated aortas was Ϸ60% higher and the mean lesion area in serial sections of the aortic valves 45% larger.

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“…Several lines of evidence that include epidemiological data, transgenic animal studies, and, more recently, prospective human clinical trials (2)(3)(4)(5)(6) indicate that increased plasma HDL levels protect against the development of atherosclerosis. One of several proposed functions of HDL as an anti-atherogenic lipoprotein is to facilitate reverse cholesterol transport, a process by which cholesterol is transported from peripheral cells to the liver for removal from the body (7,8).…”

mentioning

confidence: 99%

Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice

Lambert

Sakai

Vaisman

et al. 2001

Journal of Biological Chemistry

117

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To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (؊70 to ؊94%) and non-HDL cholesterol (؊48 to ؊85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (؊35% to ؊99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.As the key enzyme responsible for the esterification of free cholesterol present in circulating lipoproteins, LCAT 1 plays a major role in HDL metabolism (1). Several lines of evidence that include epidemiological data, transgenic animal studies, and, more recently, prospective human clinical trials (2-6) indicate that increased plasma HDL levels protect against the development of atherosclerosis. One of several proposed functions of HDL as an anti-atherogenic lipoprotein is to facilitate reverse cholesterol transport, a process by which cholesterol is transported from peripheral cells to the liver for removal from the body (7,8). LCAT may play a major role in this process by maintaining a free cholesterol gradient between peripheral cells and the HDL particle surface, thus promoting free cholesterol efflux (1). The newly generated cholesteryl esters (CE) accumulating in the HDL core may be transferred directly to the liver via whole particle and/or selective uptake (9, 10). Alternatively HDL-CE may be transferred to apoB-containing lipoproteins as a result of the activity of cholesterol ester transfer protein (CETP) (8).The important role that LCAT plays in HDL metabolism has been established by the ide...

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Inhibition of Atherosclerosis Development in Cholesterol-Fed Human Apolipoprotein A-I–Transgenic Rabbits

Abstract: Overexpression of human apo A-I in rabbits inhibits the development of atherosclerosis in this animal model that resembles, in many respects, human atherosclerosis.

Cited by 209 publications

References 33 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

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

Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice

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