Identification of Pathways for Atherosclerosis in Mice

Wang, Susanna S.; Schadt, Eric E.; Wang, Hui; Wang, Xuping; Ingram‐Drake, Leslie; Shi, Weibin; Drake, Thomas A.; Lusis, Aldons J.

doi:10.1161/circresaha.107.152975

Cited by 102 publications

(80 citation statements)

References 62 publications

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“…The BxH Apoe -/-cross was constructed using 2 strains of mice that differ dramatically in lesion susceptibility: C3H (resistant) and B6 (susceptible). The mean lesion size in F2 females was 244,524 ± 8,694 μm 2 , whereas the mean for F2 males was 176,424 ± 7,220 μm 2 (P < 1 × 10 -4 , Student's t test) (10). By integrating genotype, gene expression, and aortic lesion size measured in 334 F2 mice and testing causal, reactive, and independent models using the LCMS procedure, we identified 292 genes supported as causal for aortic lesions at a false discovery rate (FDR) of less than 5%.…”

Section: Identification Of Genes Testing Causal For Aortic Lesions Inmentioning

confidence: 87%

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Identification and validation of genes affecting aortic lesions in mice

Yang¹,

Peterson²,

Thieringer³

et al. 2010

J. Clin. Invest.

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Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli hoodbased model selection method to infer genedisease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genomewide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosisrelated pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of cau sality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.

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Section: Identification Of Genes Testing Causal For Aortic Lesions Inmentioning

confidence: 87%

“…10,11). We identified 292 genes that were supported as causal for aortic lesions from the adipose and liver of this cross.…”

Section: Introductionmentioning

confidence: 99%

Identification and validation of genes affecting aortic lesions in mice

Yang¹,

Peterson²,

Thieringer³

et al. 2010

J. Clin. Invest.

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“…Early studies of the arterial wall of the two strains focused on one or a few genes of interest (13,14), thus severely narrowing the scope of the findings. Due to the polygenic nature of atherosclerosis, recent studies have taken advantage of the microarray technology to examine genome-wide gene expression differences between the strains (18,20). The genome-wide transcriptional profiling of aortas from wild-type B6 and C3H mice identified a list of candidate genes relevant to growth, differentiation, inflammation, cathecholamine synthesis, phosphatase activity, peroxisome function, insulin-like growth factor activity, and antigen presentation (18).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, apoE Ϫ/Ϫ mice develop lesions that are similar in many aspects to human lesions (7). In an intercross derived from B6.apoE Ϫ/Ϫ and C3H.apoE Ϫ/Ϫ parental strains, Wang et al (20) performed expression array analysis of the liver and adipose tissues and identified Ͼ 10,000 expression quantitative trait loci. However, the vessel wall, a tissue most relevant to atherosclerosis, had not been examined.…”

Section: Discussionmentioning

confidence: 99%

Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility

Yuan¹,

Miyoshi²,

Bao³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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W. Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility. Am J Physiol Heart Circ Physiol 296: H1336 -H1343, 2009. First published March 20, 2009 doi:10.1152/ajpheart.01095.2008.-Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit a marked difference in atherosclerotic lesion formation when deficient in apolipoprotein E (apoE Ϫ/Ϫ ), and the arterial wall has been identified as a source of the difference in atherosclerosis susceptibility. In the present study, differences in gene expression in aortic walls of the two strains were analyzed by microarrays. Total RNA was extracted from the aorta of 6-wk-old female B6 and C3H apoE Ϫ/Ϫ mice fed a chow or Western diet. There were 1,514 genes in chow fed mice and 590 genes in Western fed mice that were found to be differentially expressed between the two strains. Pathway analysis of differentially expressed genes suggested a role for the calcium signaling pathway in regulating atherosclerosis susceptibility. Oxidized LDL (oxLDL) induced a dose-dependent rise in cytosolic calcium levels in B6 endothelial cells. oxLDL-induced monocyte chemoattractant protein-1 production was inhibited by pretreatment with calcium chelator EGTA or intracellular calcium trapping compound BAPTA, indicating that calcium ions mediate the effect of oxLDL on monocyte chemoattractant protein-1 induction. The present findings demonstrate involvement of the calcium signaling pathway in the inflammatory process of atherogenesis. gene profiling; genetic susceptibility; monocyte chemoattractant protein-1 ATHEROSCLEROSIS IS A CHRONIC inflammatory disease of the large-and medium-sized arteries involving numerous genes, as well as their interactions with the environment. The mouse has been a powerful force in elucidating the genetic basis of atherogenesis. More than 80 genes have been confirmed to play a role in atherosclerosis by using gene-targeted or transgenic mice (21). Inbred mouse strains that display quantitative differences in susceptibility to atherosclerosis or associated traits have also been used to search for genes and pathways that give rise to the traits. C57BL/6 (B6) and C3H/HeJ (C3H) mice are two inbred strains that exhibit marked differences in atherosclerosis susceptibility when fed an atherogenic diet or when deficient in apolipoprotein E (apoE Ϫ/Ϫ ) (8,14). Strain B6 readily develops atherosclerosis, while strain C3H is highly resistant to it. We have observed various differences between the two strains in atherogenic processes involving the arterial wall, including differences in the retention of apoB-containing lipoproteins in the arterial wall (2), in the capacity to oxidize low-density lipoprotein (LDL) (2), and in the expression of proinflammatory genes upon stimulation with oxidized LDL (13). Through aorta transplantation, whereby aortic segments from B6.apoE Ϫ/Ϫ and C3H.apoE Ϫ/Ϫ mice were transplanted into the infrarenal aorta of their F 1 strains, we have demonstrated that th...

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“…For this, we repeatedly crossed the mutation, originally on a mixed C57BL/6JxC3HeB/FeJ background, to inbred C57BL/6J mice. We felt this was important as C3H mice are highly resistant to atherosclerosis and nearly a dozen major loci contribute to the differences in susceptibility between C57BL/6 and C3H mice on an apoE null background ( 18 ). After 10 generations of backcrossing, we intercrossed heterozygous mice.…”

Section: Dose-dependent Effects Of An Csf-1 Defi Ciency In a Defi Nedmentioning

confidence: 99%

Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis

Shaposhnik

Wang

Lusis

2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org ated by its receptor, the tyrosine kinase proto-oncogene c-fms (also known as Csf1r ). Interleukin-34 (IL-34) has been recently identifi ed as another ligand for CSF1-R; however, its role in atherosclerosis has yet to be elucidated. Infl ammatory disorders that display elevated levels of CSF-1 include arthritis, obesity, and atherosclerosis ( 7 ). The potential involvement of CSF-1 in atherosclerosis was fi rst suggested by the observation that CSF-1 is induced in endothelial cells by treatment with oxidized lipids ( 8 ) and is expressed at high levels in atherosclerotic lesions ( 8, 9 ). Subsequently, it was shown that osteopetrotic ( op/op ) mice carrying a Csf1 null mutation, either on an apolipoprotein E (apoE) Ϫ / Ϫ or a low density lipoprotein receptor null) background, showed a dramatic decrease in the size of atherosclerotic lesions ( 10-12 ).Several signifi cant issues concerning the role of CSF-1 in atherogenesis remain unresolved. First, the mechanism by which the CSF-1 defi ciency contributes to lesion development remains unclear. Because CSF-1 infl uences monocyte/macrophage growth and survival, likely mechanisms include decreased numbers of circulating monocytes; decreased monocyte recruitment to the artery wall; decreased monocyte/macrophage proliferation; decreased macrophage uptake of oxidized lipids; and increased monocyte/macrophage foam cell necrosis/apoptosis. Second, the source of the CSF-1 critical for lesion formation is unclear. Both macrophages and endothelial cells (EC) Abstract Previous studies have shown that colony stimulating factor-1 (CSF-1) defi ciency dramatically reduced atherogenesis in mice. In this report we investigate this mechanism and explore a therapeutic avenue based on inhibition of CSF-1 signaling. Lesions from macrophage colony stimulating factor-1 ( Csf1) +/ Ϫ mice showed increased numbers of apoptotic macrophages, decreased overall macrophage content, and infl ammation. In vitro studies indicated that CSF-1 is chemotactic for monocytes. Bone marrow transplantation studies suggested that vascular cell-derived, rather than macrophage-derived, CSF-1 is responsible for the effect on atherosclerosis. Consistent with previous studies, CSF-1 affected lesion development in a dose-dependent manner, suggesting that pharmacological inhibition of CSF-1 might achieve similar results. Indeed, we observed that treatment of hyperlipidemic mice with a CSF-1 receptor kinase inhibitor inhibited plaque progression. This observation was accompanied by a reduction in the expression of adhesion factors (ICAM-1), macrophage markers (F4/80), infl ammatory cytokines (Il-6, Il-1 ␤ ), and macrophage matrix degradation enzymes (MMP-9). We conclude that the M-CSF pathway contributes to monocyte recruitment and macrophage survival and that this pathway is a potential target for therapeutic intervention. -Shaposhnik, Z., X. Wang, and A. J. Lusis. Arterial colony stimulating factor-1 infl uences atherosclerotic lesions by regulating monocyte ...

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Identification of Pathways for Atherosclerosis in Mice

Cited by 102 publications

References 62 publications

Identification and validation of genes affecting aortic lesions in mice

Identification and validation of genes affecting aortic lesions in mice

Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility

Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis

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