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

Dansky, Hayes M.; Charlton, Sherri A.; Sikes, John L.; Heath, Simon; Simantov, Ronit; Levin, Lawrence F.; Shu, Pei; Moore, Karen J.; Breslow, Jan L.; Smith, Jonathan

doi:10.1161/01.atv.19.8.1960

Cited by 151 publications

(146 citation statements)

References 65 publications

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“…Infected animals presented a reduction in the serum VLDL cholesterol fraction that represents an important proatherogenic lipoprotein in mice. These results agree with those obtained by Paigen et al (29), Dansky et al (6), and Grimsditch et al (19), who suggested that the correlation between blood cholesterol and atherosclerosis is not evident in cases of concomitant infection.…”

Section: Discussionsupporting

confidence: 92%

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Portugal¹,

Fernandes²,

César³

et al. 2004

Infect Immun

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Toxoplasma gondii is an intracellular protozoan that elicits a potent inflammatory response during the acute phase of infection. Herein, we evaluate whether T. gondii infection alters the natural course of aortic lesions. ApoE knockout mice were infected with T. gondii, and at 5 weeks of infection, serum, feces, and liver cholesterol; aortic lesion size, cellularity, and inflammatory cytokines; and levels of serum nitrite and gamma interferon (IFN-␥) were analyzed. Our results showed that serum cholesterol and atherogenic lipoproteins were reduced after T. gondii infection. The reduction of serum levels of total cholesterol and atherogenic lipoproteins was associated with increases in the aortic lesion area, numbers of inflammatory cells, and expression of monocyte chemoattractant protein 1 and inducible nitric oxide synthase mRNA in the site of lesions as well as elevated concentrations of IFN-␥ and nitrite in sera of T. gondii-infected animals. These results suggest that infection with T. gondii accelerates atherosclerotic development by stimulating the proinflammatory response and oxidative stress, thereby increasing the area of aortic lesion.Atherosclerotic lesions are characterized by progressive accumulation of lipids, macrophages, natural killer (NK) cells, T and B cells, smooth muscle cells, and fibroproliferative elements in the intima of arteries (30). However, hypercholesterolemia and, mainly, high serum levels of low-density lipoprotein (LDL) are considered an absolute prerequisite for lesion establishment. Several genetic and environmental risk factors have been found to contribute to the development of atherosclerosis (2,22,27,33). Among these factors, the immune system is one of the most important. Innate and adaptive immune responses modulate both the rate of lesion progression and composition of atherosclerotic lesions. ApoE knockout (KO) mice crossed into a recombination activating gene (Rag)-deficient background, which lack B and T lymphocytes, had an 80% decrease in the extension of atherosclerotic lesions (32). In addition, crosses of ApoE KO mice with different types of B-or T-cell-deficient mice also decreased atherosclerotic lesions (2,22,40). Inflammatory cytokines and chemokines, such as gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), TNF-␤, interleukin-12 (IL-12), IL-1␤, and monocyte chemoattractant protein 1 (MCP-1), increase the influx of monocyte into the endothelium, an important step in fatty streak formation (21,24,39). Therefore, atherosclerosis is now considered a chronic inflammatory disease, and systemic infections are thought to play an important role in initiating and/or perpetuating the pathophysiology of aortic lesions. In fact, some studies indicate that bacterial and viral pathogens could be responsible for atherosclerotic development (35). Sunnemark et al. (37) have shown that the combination of an infection of the protozoan parasite Trypanosoma cruzi with an atherogenic diet induced atherosclerotic lesions in the aorta of atherosclerosis-resistant CBA/...

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Section: Discussionsupporting

confidence: 92%

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Portugal¹,

Fernandes²,

César³

et al. 2004

Infect Immun

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“…While increased apoB-48 containing lipoproteins are atherogenic in the 129-apoE mice, increased HDL-cholesterol may overcome this adverse effect. The inverse relationship between elevated plasma lipids and reduced atherosclerosis has been reported previously in apoE-/-mice that have been backcrossed onto an FVB/NJ background (18). These authors analyzed an F2 population between apoE-/-mice on the FVB and B6 backgrounds, and found no correlation between the plasma levels of lipid/lipoproteins and the size of lesions at aortic root.…”

Section: Discussionmentioning

confidence: 78%

Anatomical differences and atherosclerosis in apolipoprotein E-deficient mice with 129/SvEv and C57BL/6 genetic backgrounds

et al. 2007

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There are well-known genetic background effects on atherosclerosis susceptibility in mice. To study the basis of these effects, we have generated the apolipoprotein E-null mutation in mouse embryonic stem cells of 129/SvEv origin, maintained it in the inbred strain (129-apoE), and compared these mice with those previously made in strain 129/Ola and backcrossed to a C57BL/6 genetic background (B6-apoE). Plasma cholesterol and triglyceride levels in the apoE-129 mice are twice the levels in apoE-B6, and both VLDL/chylomicron remnants and HDL particles are increased. Regression analysis of plaque size relative to the age of mice suggests that the initiation of atherosclerotic plaque development at the aortic root is slower in 129-apoE mice (intercept at 3.9 mo in females and 4.1 mo in males) than in B6-apoE mice (1.3 mo in females and 2.8 mo in males). In contrast, 129-apoE mice develop extensive plaques in the aortic arches earlier than B6-apoE mice. Distinct differences in the geometry of the aortic arch between the two strains suggest that anatomical differences may contribute to the effects of genetic background on atherosclerosis. The 129-apoE/B6-apoE pair thus provides a tool to study factors governing the relation between arterial geometry and the location of plaque development. Keywordsanimal model; atherosclerotic plaque distribution; cholesterol; aortic arch; aortic root; inbred mouse strain; ductus arteriosus Well-characterized animal models are essential for the study of common human diseases such as those involving the cardiovascular system. The first practical mouse model of atherosclerosis was developed by inactivating the gene coding for apolipoprotein E (apoE) (1-3). ApoE plays a central role in lipoprotein metabolism and is required for efficient receptor-mediated plasma clearance by the liver of chylomicron remnants and very low-density lipoprotein (VLDL)-remnant particles (4). Lack of apoE in the mutant mice results in an increased accumulation of cholesterol-enriched remnant particles and four times normal plasma cholesterol levels even Correspondence to: Dr. Nobuyo Maeda, Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. Phone: 919-966-6912, Fax: 919-966-8800. E-mail: nobuyo@med.unc.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. when the mice are fed regular low-fat, low-cholesterol chow. The apoE-deficient mice spontaneously develop atherosclerotic plaques similar to those seen in humans (5,6), with the exception that the spontaneo...

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Section: Discussionmentioning

confidence: 99%

“…Different strains of mice display differential atherosusceptibility (38)(39)(40). The lesion mean area is 7-to 9-fold and 3.5-fold higher in ApoE Ϫ/Ϫ mice raised on C57BL͞6 background when fed chow and HFD, respectively, compared with ApoE Ϫ/Ϫ mice raised on FVB͞N background (39). The fact that AEBP1 TG mice were generated on FVB͞N background limits our ability to investigate a direct role of AEBP1 in the development of atherosclerosis, because mice are highly resistant to the development of atherosclerosis under normal conditions (41).…”

Section: Discussionmentioning

confidence: 99%

Adipocyte enhancer-binding protein 1 is a potential novel atherogenic factor involved in macrophage cholesterol homeostasis and inflammation

Majdalawieh

Zhang

Fuki

et al. 2006

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

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Peroxisome proliferator-activated receptor ␥1 (PPAR␥1) and liver X receptor ␣ (LXR␣) play pivotal roles in macrophage cholesterol homeostasis and inflammation, key biological processes in atherogenesis. Herein we identify adipocyte enhancer-binding protein 1 (AEBP1) as a transcriptional repressor that impedes macrophage cholesterol efflux, promoting foam cell formation, via PPAR␥1 and LXR␣ down-regulation. Contrary to AEBP1 deficiency, AEBP1 overexpression in macrophages is accompanied by decreased expression of PPAR␥1, LXR␣, and their target genes ATP-binding cassette A1, ATP-binding cassette G1, apolipoprotein E, and CD36, with concomitant elevation in IL-6, TNF-␣, monocyte chemoattractant protein 1, and inducible NO synthase levels. AEBP1, but not the C-terminally truncated DNA-binding domain mutant (AEBP1 ⌬Sty ), represses PPAR␥1 and LXR␣ in vitro. Expectedly, AEBP1-overexpressing transgenic (AEBP1 TG ) macrophages accumulate considerable amounts of lipids compared with AEBP1 nontransgenic macrophages, making them precursors for foam cells. Indeed, AEBP1-overexpressing transgenic macrophages exhibit diminished cholesterol efflux compared with AEBP1 nontransgenic macrophages, whereas AEBP1-knockout (AEBP1 ؊/؊ ) macrophages exhibit enhanced cholesterol efflux compared with wild-type (AEBP1 ؉/؉ ) macrophages. Our in vitro and ex vivo experimental data strongly suggest that AEBP1 plays critical regulatory roles in macrophage cholesterol homeostasis, foam cell formation, and proinflammation. Thereby, we speculate that AEBP1 may be critically implicated in the development of atherosclerosis, and it may serve as a molecular target toward developing antiinflammatory, antiatherogenic therapeutic approaches.atherogenesis ͉ cholesterol efflux ͉ liver X receptor ␣ ͉ peroxisome proliferator-activated receptor ␥

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

Cited by 151 publications

References 65 publications

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Anatomical differences and atherosclerosis in apolipoprotein E-deficient mice with 129/SvEv and C57BL/6 genetic backgrounds

Adipocyte enhancer-binding protein 1 is a potential novel atherogenic factor involved in macrophage cholesterol homeostasis and inflammation

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