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Transcriptional profiling of foam cells in response to hypercholesterolemia.

ABSTRACT: Hypercholesterolemia is a main risk factor for atherosclerosis development. Arterial macrophages, or foam cells, take-up and process lipoprotein particles deposited in arteries, and store much of the cholesterol carried by these particles in their cytoplasm. However, the effects of exposure to different cholesterol levels on foam cells remain poorly understood. Given the remarkable plasticity of macrophages in response to environmental variables, studies on macrophage biology should ideally be performed in the environment where they exert their physiological functions, namely atherosclerotic lesions in the case of foam cells. We used a mouse model of atherosclerosis, the apolipoprotein E-deficient mouse, to study in vivo the transcriptional response of foam cells to short- and long-term elevations in plasma cholesterol, induced by feeding mice a western type diet. The microarray data sets from this study have been deposited in NCBI's Gene Expression Omnibus under the accession number GSE70619. Here we provide detailed information on the experimental set-up, on the isolation of RNA by laser capture microdissection, and on the methodology used for RNA amplification and analysis by microarray and quantitative real-time PCR.

SUBMITTER: Goo YH

PROVIDER: S-EPMC4925893 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Transcriptional profiling of foam cells in response to hypercholesterolemia.

Goo Young-Hwa YH Yechoor Vijay K VK Paul Antoni A

Genomics data 20160620

Hypercholesterolemia is a main risk factor for atherosclerosis development. Arterial macrophages, or foam cells, take-up and process lipoprotein particles deposited in arteries, and store much of the cholesterol carried by these particles in their cytoplasm. However, the effects of exposure to different cholesterol levels on foam cells remain poorly understood. Given the remarkable plasticity of macrophages in response to environmental variables, studies on macrophage biology should ideally be p ...[more]

PMID: 27408807

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Project description:BackgroundCardiovascular diseases remain the leading cause of morbidity and mortality worldwide, most of which are caused by atherosclerosis. Discerning processes that participate in macrophage-to-foam cell formation are critical for understanding the basic mechanisms underlying atherosclerosis. To explore the molecular mechanisms of foam cell formation, differentially expressed proteins were identified.MethodsHuman peripheral blood mononuclear cells were stimulated with macrophage colony-stimulating factor, and obtained macrophages were transformed into foam cells by oxidized low-density lipoprotein. Tandem mass tag (TMT) labeling combined with mass spectrometry was performed to find associations between foam cell transformation and proteome profiles.ResultsTotally, 5146 quantifiable proteins were identified, among which 1515 and 182 differentially expressed proteins (DEPs) were found in macrophage/monocyte and foam cell/macrophage, respectively. Subcellular localization analysis revealed that downregulated DEPs of macrophages/monocytes were mostly located in the nucleus, whereas upregulated DEPs of foam cells/macrophages were mostly extracellular or located in the plasma membrane. Functional analysis of DEPs demonstrated that cholesterol metabolism-related proteins were upregulated in foam cells, whereas immune response-related proteins were downregulated in foam cells. The protein interaction network showed that the DEPs with the highest interaction scores between macrophages and foam cells were mainly concentrated in lysosomes and the endoplasmic reticulum.ConclusionsProteomics analysis suggested that cholesterol metabolism was upregulated, while the immune response was suppressed in foam cells. KEGG enrichment analysis and protein-protein interaction analysis indicated that DEPs located in the endoplasmic reticulum and lysosomes might be key drivers of foam cell formation. These data provide a basis for identifying the potential proteins associated with the molecular mechanism underlying macrophage transformation to foam cells.

Project description:BACKGROUND: Marrow-derived stromal cells (MSCs) maintain the capability of self-renewal and differentiation into multiple lineages in adult life. Age-related changes are recognized by a decline in the stemness potential that result in reduced regeneration potential of the skeleton. To explore the molecular events that underline skeletal physiology during aging we catalogued the profile of gene expression in ex vivo cultured MSCs derived from 3 and 15 month old rats. The ex vivo cultured cells were analyzed following challenge with or without Dexamethasone (Dex). RNA retrieved from these cells was analyzed using Affymetrix Gene Chips to compare the effect of Dex on gene expression in both age groups. RESULTS: The molecular mechanisms that underline skeletal senescence were studied by gene expression analysis of RNA harvested from MSCs. The analysis resulted in complex profiles of gene expression of various differentiation pathways. We revealed changes of lineage-specific gene expression; in general the pattern of expression included repression of proliferation and induction of differentiation. The functional analysis of genes clustered were related to major pathways; an increase in bone remodeling, osteogenesis and muscle formation, coupled with a decrease in adipogenesis. We demonstrated a Dex-related decrease in immune response and in genes that regulate bone resorption and an increase in osteoblastic differentiation. Myogenic-related genes and genes that regulate cell cycle were induced by Dex. While Dex repressed genes related to adipogenesis and catabolism, this decrease was complementary to an increase in expression of genes related to osteogenesis. CONCLUSION: This study summarizes the genes expressed in the ex vivo cultured mesenchymal cells and their response to Dex. Functional clustering highlights the complexity of gene expression in MSCs and will advance the understanding of major pathways that trigger the natural changes underlining physiological aging. The high throughput analysis shed light on the anabolic effect of Dex and the relationship between osteogenesis, myogenesis and adipogenesis in the bone marrow cells.

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Transcriptional profiling of foam cells in response to hypercholesterolemia.

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Transcriptional profiling of foam cells in response to hypercholesterolemia.

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