Transcriptome profile of macrophages from atherosclerosis-sensitive and atherosclerosis-resistant mice

Smith, Jonathan; Peng, Dao Quan; Dansky, Hayes M.; Settle, Megan; Baglione, Julie; Goff, Wilfried Le; Chakrabarti, Enakshi; Xu, Yaomin; Peng, Xuejun

doi:10.1007/s00335-005-0099-7

Cited by 16 publications

(12 citation statements)

References 21 publications

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“…Mouse bone-marrow macrophages (BMM) were derived from femurs of freshly sacrificed mice as described by Smith et al11 and Hume et al12 with minor modifications. Briefly, bone marrow was flushed with PBS supplemented with 50U/ml penicillin / 50ug/ml streptomycin antibiotics and 0.1% FBS.…”

Section: Methodsmentioning

confidence: 99%

Moderately Decreased Cholesterol Absorption Rates Are Associated With a Large Atheroprotective Effect

Greenberg

Smith

Sehayek

2009

ATVB

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Objective-Human treatment with ezetimibe results in a moderate 50% to 54% decrease in cholesterol absorption and a 15% to 20% decrease in plasma LDL-cholesterol levels; nevertheless, the efficacy of ezetimibe therapy has been recently challenged by the ENHANCE trial. We examined the efficacy of a moderate decrease in cholesterol absorption in preventing atherosclerosis formation in the mouse. Methods and Results-Congenic 14DKK animals, consisting of a castaneus (CASA/Rk) chromosome 14 interval introgressed onto the C57BL/6J background, displayed a moderate decrease in cholesterol absorption rates. The effect of moderately decreased absorption on atherosclerosis formation was determined in 14DKK apolipoprotein E knockouts (14DKK-apoEKO). When compared to chow diet-fed control apoEKO mice, congenic 14DKK-apoEKO displayed a moderate 41% decrease in cholesterol absorption rates, 30% to 37% decrease in plasma cholesterol levels, and a 70% decrease in atherosclerosis formation. Studies on cholesterol efflux and reverse cholesterol transport (RCT) from 14DKK bone marrow-derived macrophages rejected a 14DKK intervaldependent atheroprotective effects that operate in macrophages. In contrast, 14DKK-apoEKO congenics were characterized by a 60% increase in RCT from peripheral tissue macrophages. Conclusions-These studies strongly suggest that moderately decreased cholesterol absorption rates result in a large atheroprotective effect attributable to a decrease in plasma cholesterol levels and an increase in RCT from peripheral tissue macrophages. Key Words: cholesterol Ⅲ absorption Ⅲ atherosclerosis Ⅲ reverse cholesterol transport Ⅲ macrophage T he absorption of cholesterol from the intestine is an important determinant of plasma cholesterol levels, a well-established risk factor for atherosclerotic cardiovascular diseases. Clinical studies that examined the effect of a specific and potent cholesterol absorption inhibitor, ezetimibe, on cholesterol absorption and plasma cholesterol levels reported a proportional reduction of 50% to 54% in absorption rates, from 50% to 23%, and a decrease of 15% to 20% in plasma low-density lipoprotein cholesterol (LDL-cholesterol) levels. 1,2 Previous cholesterol-lowering trials indicated that every 1% decrease in plasma LDLcholesterol is expected to decrease the risk for major cardiovascular events by 1%. Based on these estimates treatment with ezetimibe is expected to decrease the risk for cardiovascular events by 15% to 20%, a premise that is currently tested by several ongoing clinical trials. 3,4 Interestingly, and in striking contrast with these expectations, the recently published ENHANCE trial is challenging this view. 5 This trial compared the effect of treatment with simvastatin to combined therapy with simvastatin plus ezetimibe on atherosclerosis formation in heterozygous familial hypercholesterolemic patients. Interestingly, when compared to the simvastatin-treated group, the addition of ezetimibe resulted in further significant decrease in plasma LDL-cholesterol levels; however...

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Section: Methodsmentioning

confidence: 99%

Moderately Decreased Cholesterol Absorption Rates Are Associated With a Large Atheroprotective Effect

Greenberg

Smith

Sehayek

2009

ATVB

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“…Cell lines that have been generated from mouse strains can also be used for genetic studies 70,71 . The idea behind these studies is that cell lines are generated from each mouse strain and that phenotyping is carried out on these cell lines.…”

Section: Future Directionsmentioning

confidence: 99%

Genome-wide association studies in mice

2012

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Genome-wide association studies (GWASs) have transformed the field of human genetics and have led to the discovery of hundreds of genes that are implicated in human disease. The technological advances that drove this revolution are now poised to transform genetic studies in model organisms, including mice. However, the design of GWASs in mouse strains is fundamentally different from the design of human GWASs, creating new challenges and opportunities. This Review gives an overview of the novel study designs for mouse GWASs, which dramatically improve both the statistical power and resolution compared to classical gene-mapping approaches.

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“…These variations can be estimated by transcriptomic analyses using microarrays that allow the screening of a large number of changes in mRNA expression. Microarrays have been widely used in immune cells to study the host response at the gene transcription level in several situations such as bacterial infections (Malcolm et al 2003;Ge et al 2010), stimulation by various components (Kawano et al 2010), atherosclerosis (Smith et al 2006) or ischemic stroke (Tang et al 2006).…”

Section: Communicated By G Materamentioning

confidence: 99%

Transcriptomic and nuclear architecture of immune cells after LPS activation

et al. 2011

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Changes in the nuclear positioning of specific genes, depending on their expression status, have been observed in a large diversity of physiological processes. However, gene position is poorly documented for immune cells which have been subjected to activation following bacterial infection. Using a pig model, we focused our study on monocyte-derived macrophages and neutrophils, as they are the first lines of defence against pathogens. We examined whether changes in gene expression due to LPS activation imply that genes have repositioned in the nuclear space. We first performed a transcriptomic analysis to identify the differentially expressed genes and then analysed the networks involved during lypopolysaccharide/interferon gamma activation in monocyte-derived macrophages. This allowed us to select four up-regulated (IL1β, IL8, CXCL10 and TNFα) and four down-regulated (VIM, LGALS3, TUBA3 and IGF2) genes. Their expression statuses were verified by quantitative real-time RT-PCR before studying their behaviour in the nuclear space during macrophage activation by means of 3D fluorescence in situ hybridization. No global correlation was found between gene activity and radial positioning. Only TNFα belonging to the highly transcribed MHC region on chromosome 7 became more peripherally localized in relation to the less decondensed state of its chromosome territory (CT) in activated macrophages. The analysis of gene positioning towards their CT revealed that IL8 increases significantly its tendency to be outside its CT during the activation process. In addition, the gene to CT edge distances increase for the three up-regulated genes (IL8, CXCL10 and TNFα) among the four analysed. Contrarily, the four down-regulated genes did not change their position. The analysis of gene behaviour towards their CT was extended to include neutrophils for three (TNFα, IL8 and IL1β) up- and two (IGF2 and TUBA3) down-regulated genes, and similar results were obtained. The analysis was completed by studying the four up-regulated genes in fibroblasts, not involved in immune response. Our data suggest that relocation in the nuclear space of genes that are differentially expressed in activated immune cells is gene and cell type specific but also closely linked to the entire up-regulation status of their chromosomal regions.

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Transcriptome profile of macrophages from atherosclerosis-sensitive and atherosclerosis-resistant mice

Cited by 16 publications

References 21 publications

Moderately Decreased Cholesterol Absorption Rates Are Associated With a Large Atheroprotective Effect

Moderately Decreased Cholesterol Absorption Rates Are Associated With a Large Atheroprotective Effect

Genome-wide association studies in mice

Transcriptomic and nuclear architecture of immune cells after LPS activation

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