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Similarities and differences in the transcriptome of human atherosclerotic and non-atherosclerotic macrophages

ABSTRACT: Phenotypic and functional diversity between macrophage subpopulations reflects their plasticity to respond to microenvironmental signals. Apart from detecting differences in expression profiles, the comparison of the transcriptomes of different macrophage populations may also allow the definition of molecular similarities between these subsets. Transcriptome analysis of human Kuppfer cells, alveolar, splenic and atherosclerotic plaque residing macrophages using microarrays, identified 42 genes that are specifically expressed in atherosclerotic plaque macrophages. We also focus on the similarities in the transcriptome of human Kupffer cells, alveolar, splenic and atherosclerotic plaque residing macrophages. We hypothesized that these macrophages share a common expression signature. We performed microarray analysis on mRNA from these macrophage subsets (n = 4 patients) and developed a novel statistical method to identify genes with significantly similar expression levels. This method calculates the maximum difference in expression level of a gene, based on the estimated confidence interval on that genes expression variance. We listed the genes by equivalence ranking relative to their expression level. False Discovery Rate (FDR) estimation was used to determine significance. We identified 500 genes that had significantly equivalent expression levels in the macrophage subsets at an 5.5% FDR using a 90% confidence interval. Equivalently expressed genes, identified by this newly developed method, may not only help to dissect common molecular mechanisms, but also to identify cell or condition specific sets of marker genes that can be used for drug targeting and molecular imaging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE7074 | GEO | 2007/05/31

SECONDARY ACCESSION(S): PRJNA98483

REPOSITORIES: GEO

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Project description:Objective: Resident macrophages play an important role in atheromatous plaque rupture. The macrophage gene expression signature associated with plaque rupture is incompletely defined due to the complex cellular heterogeneity in the plaque. We aimed to characterise differential gene expression in resident plaque macrophages from ruptured and stable human atheromatous lesions. A cell-specific approach has the potential to address the question of gene expression differences between particular cell types in stable and unstable plaques with greater precision than approaches based on the study of whole plaques. Using laser micro-dissection, we isolated total RNA from macrophage-rich regions of stable and ruptured human atheromatous plaques derived from carotid endarterectomy samples which were comprehensively characterized using clinical, radiological and histological criteria, and carried out genome-wide gene expression profiling using microarrays. Results: The profiles were characteristic of activated macrophages. At a false discovery rate of 10%, 914 genes were differentially expressed between stable and ruptured plaques. The findings were confirmed in fourteen further stable and ruptured samples for a subset of eleven genes with the highest expression differences (p<0.05). Pathway analysis revealed that components of the PPAR/Adipocytokine signaling pathway were the most significantly upregulated in ruptured compared to stable plaques (p=5.4x10-7). Two key components of the pathway, fatty-acid binding-protein 4 (FABP4) and leptin, showed nine-fold (p=0.0086) and five-fold (p=0.0012) greater expression respectively in macrophages from ruptured plaques. Conclusions: We found differences in gene expression signatures between macrophages isolated from stable and ruptured human atheromatous plaques. Our findings indicate the involvement of FABP4 and leptin in the progression of atherosclerosis and plaque rupture, and suggest that down-regulation of PPAR/adipocytokine signaling within plaques may have therapeutic potential. Methods: We performed genome-wide expression analyses of isolated macrophage-rich regions of stable and ruptured human atherosclerotic plaques. Plaques present in carotid endarterectomy specimens were designated as stable or ruptured using clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from 5 ruptured and 6 stable plaques by laser micro-dissection. Total RNA were subjected to two cycles of linear amplification. Transcriptional profiling was performed using Affymetrix HG-U133 plus 2.0 GeneChip arrays.

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Similarities and differences in the transcriptome of human atherosclerotic and non-atherosclerotic macrophages

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