Atherosclerosis susceptibility differences among progenitors of recombinant inbred strains of mice.

Paigen, Beverly; Ishida, Brian Y.; Verstuyft, Judy G.; Winters, R B; Albee, Deborah

doi:10.1161/01.atv.10.2.316

Cited by 253 publications

(169 citation statements)

References 11 publications

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“…To examine the role of apoE secretion by the macrophage in early atherogenesis, we transplanted C57BL/6 mice, an inbred strain that is susceptible to atherosclerosis (27), with bone marrow from apoE(Ϫ/Ϫ) mice, creating a de facto macrophage-specific knock-out of apoE. After lethal irradiation [9 grays], 8-week-old female C57BL/6 mice were transplanted with 5 ϫ 10 6 bone marrow cells from either apoE(Ϫ/Ϫ) mice (n ϭ 14, experimental group) or wild-type apoE(ϩ/ϩ) mice (n ϭ 11, control group).…”

Section: Resultsmentioning

confidence: 99%

“…A 100-l aliquot of mouse serum was injected onto the column and separated with a buffer containing 0.15 M NaCl, 0.01 M Na 2 HPO 4 , 0.1 mM EDTA, pH 7.5, at a flow rate of 0.5 ml/min. Fifty fractions of 0.5 ml each were collected, with the lipoproteins being contained within tubes [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Protein Electrophoresis and Western Blots. The lipoproteins were extensively dialyzed in 0.15 M NaCl, 0.01 mM EDTA, at 4ЊC, and then either concentrated using Centricon filters (Amicon) and used for agarose gel electrophoresis, or precipitated using a 50-mg/ml solution of fumed silica (Cab-O-Sil; Sigma) and used for SDS/PAGE.…”

Section: Methodsmentioning

confidence: 99%

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Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages

Fazio

Babaev

Murray

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

271

229

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Macrophage-derived foam cells express apolipoprotein E (apoE) abundantly in atherosclerotic lesions. To examine the physiologic role of apoE secretion by the macrophage in atherogenesis, bone marrow transplantation was used to reconstitute C57BL/6 mice with macrophages that were either null or wild type for the apoE gene. After 13 weeks on an atherogenic diet, C57BL/6 mice reconstituted with apoE null marrow developed 10-fold more atherosclerosis than controls in the absence of significant differences in serum cholesterol levels or lipoprotein profiles. ApoE expression was absent in the macrophage-derived foam cells of C57BL/6 mice reconstituted with apoE null marrow. Thus, lack of apoE expression by the macrophage promotes foam cell formation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages

Fazio

Babaev

Murray

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

271

229

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“…There are several reasons why we believe this does not explain the differences in atherosclerosis development. First, the 10% contaminating background of our double knockout mice came from the 129 background, a strain that is resistant to atherosclerosis when challenged with a cholic acid-containing diet (29). Thus, the contaminating 129 background should decrease, not increase atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice

Furbee

Sawyer

Parks

2002

Journal of Biological Chemistry

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The purpose of the present study was to test the hypothesis that lecithin:cholesterol acyltransferase (LCAT) deficiency would accelerate atherosclerosis development in low density lipoprotein (LDL) receptor (LDLr؊/؊) and apoE (apoE؊/؊) knockout mice. After 16 weeks of atherogenic diet (0.1% cholesterol, 10% calories from palm oil) consumption, LDLr؊/؊ LCAT؊/؊ double knockout mice, compared with LDLr؊/؊ mice, had similar plasma concentrations of free (FC), esterified (EC), and apoB lipoprotein cholesterol, increased plasma concentrations of phospholipid and triglyceride, decreased HDL cholesterol, and 2-fold more aortic FC (142 ؎ 28 versus 61 ؎ 20 mg/g protein) and EC (102 ؎ 27 versus 61 ؎ 27 mg/g). ApoE؊/؊ LCAT؊/؊ mice fed the atherogenic diet, compared with apoE؊/؊ mice, had higher concentrations of plasma FC, EC, apoB lipoprotein cholesterol, and phospholipid, and significantly more aortic FC (149 ؎ 62 versus 109 ؎ 33 mg/g) and EC (101 ؎ 23 versus 69 ؎ 20 mg/g) than did the apoE؊/؊ mice. LCAT deficiency resulted in a 12-fold increase in the ratio of saturated ؉ monounsaturated to polyunsaturated cholesteryl esters in apoB lipoproteins in LDLr؊/؊ mice and a 3-fold increase in the apoE؊/؊ mice compared with their counterparts with active LCAT. We conclude that LCAT deficiency in LDLr؊/؊ and apoE؊/؊ mice fed an atherogenic diet resulted in increased aortic cholesterol deposition, likely due to a reduction in plasma HDL, an increased saturation of cholesteryl esters in apoB lipoproteins and, in the apoE؊/؊ background, an increased plasma concentration of apoB lipoproteins.Lecithin:cholesterol acyltransferase (LCAT, 1 EC 2.3.1.43) is a 65-kilodalton glycoprotein that is responsible for the esterification of cholesterol in plasma lipoproteins (1, 2). LCAT catalyzes a two-step reaction that hydrolyzes the sn-2 fatty acid of phospholipid, followed by a transacylation step that transfers the fatty acid to the 3␤-hydroxyl group of cholesterol, generating cholesteryl ester and lysolecithin. LCAT is activated by apolipoprotein A-I, which is the major apolipoprotein on HDL particles (3). The LCAT enzyme is important in the process of reverse cholesterol transport, which involves the movement of cholesterol from peripheral tissues back to the liver for excretion and is critical for the maintenance of normal concentration, size, and shape of plasma lipoproteins (1, 4).There are two types of LCAT deficiency in the human population, familial LCAT deficiency (FLD) and fish eye disease (FED). FLD patients are characterized by a complete lack of plasma LCAT activity, corneal opacification, anemia, proteinurea, and kidney dysfunction that can lead to renal failure (5, 6). These patients have decreased plasma total and esterified cholesterol, HDL cholesterol, apoA-I, and apoA-II concentrations and increased plasma concentrations of triglyceride, phospholipid, free cholesterol, and VLDL cholesterol. FED is characterized by a partial LCAT deficiency in which patients have corneal opacification, but no anemia or renal disease. Lipid a...

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“…7 Genetic studies of atherosclerosis, using mouse models, have mainly involved studies in which different inbred strains of mice are fed a high-fat, high-cholesterol, cholatecontaining diet developed in the laboratory of Paigen et al 8,9 By using this diet, inbred strains were characterized as susceptible, resistant, or intermediate, based on quantitative lesion area measurements. 10 Although no murine model fully recapitulates all of the features of human atherosclerosis, a potential drawback to using mice fed a high-fat, high-cholesterol, cholate-containing diet is that the diet itself is inflammatory when fed to certain strains of mice, and results in liver transaminase elevations, activation of hepatic NFB, increases in acute-phase reactants such as serum amyloid A, and liberation of inflammatory cytokines. 11 It is unclear whether this inflammation is similar or different from the inflammatory process present in human atherosclerotic lesions.…”

mentioning

confidence: 99%

Genetic Background Determines the Extent of Atherosclerosis in ApoE-Deficient Mice

Dansky

Charlton

Sikes

et al. 1999

ATVB

150

135

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Abstract-Two strains of ApoE-deficient mice were found to have markedly different plasma lipoprotein profiles and susceptibility to atherosclerosis when fed either a low-fat chow or a high-fat Western-type diet. FVB/NJ ApoE-deficient (FVB E0) mice had higher total cholesterol, HDL cholesterol, ApoA1, and ApoA2 levels when compared with C57BL/6J ApoE-deficient (C57 E0) mice. At 16 weeks of age, mean aortic root atherosclerotic lesion area was 7-to 9-fold higher in chow diet-fed C57 E0 mice and 3.5-fold higher in Western diet-fed C57 E0 mice compared with FVB E0 mice fed similar diets. Lesion area in chow diet-fed first-generation mice from a strain intercross was intermediate in size compared with parental values. The distribution of the lesion area in 150 chow diet-fed second-generation progeny spanned the range of the lesion area in both parental strains. There were no correlations between total cholesterol, non-HDL cholesterol, HDL cholesterol, ApoA1, ApoA2, ApoJ, or anti-cardiolipin antibodies and lesion area in the second-generation progeny. Thus, a genomic approach may succeed in identifying the genes responsible for the variation in atherosclerosis susceptibility in these 2 strains of ApoE-deficient mice, which could not be explained by measured plasma parameters.

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Atherosclerosis susceptibility differences among progenitors of recombinant inbred strains of mice.

Cited by 253 publications

References 11 publications

Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages

Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages

Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice

Genetic Background Determines the Extent of Atherosclerosis in ApoE-Deficient Mice

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