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Circulating Mononuclear Cell Transcriptomes in Patients with Atherosclerotic Coronary Artery Disease

ABSTRACT: Monocytes and T-cells play an important role in the development of atherosclerotic coronary artery disease (CAD). Differences in transcriptional activity of these cells might reflect the individual's atherosclerotic burden. Transcriptome analysis of circulating mononuclear cells from carefully matched atherosclerotic and control patients will potentially provide insights into the pathophysiology of atherosclerosis and supply biomarkers for diagnostic purposes. From patients undergoing coronary angiography because of anginal symptoms, we carefully matched 18 patients with severe triple-vessel CAD to 13 control patients without signs of CAD on angiography. All patients were on statin and aspirin treatment. RNA from circulating CD4+ T-cells, CD14+ monocytes, lipopolysaccharide-stimulated monocytes, macrophages and CD34+ progenitor cells was subjected to genome-wide expression analysis. Only CD14+ monocytes demonstrated that a small number of genes involved in activation was overexpressed in control patients, which was verified by real-time polymerase-chain reaction. In this pilot study, cautious matching of patients with severe atherosclerotic CAD with control patients without angiographic signs of coronary atherosclerosis did not reveal differences in transcriptional activity in four out of five different mononuclear cell types. In resting monocytes from patients without overt CAD some inflammatory genes were overexpressed as compared to patients with severe CAD. Large inter-individual variability prevented the use of single differentially expressed genes as biomarkers. Keywords: disease-state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE9820 | GEO | 2008/12/01

SECONDARY ACCESSION(S): PRJNA103779

REPOSITORIES: GEO

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Project description:Monocytes and T-cells play an important role in the development of atherosclerotic coronary artery disease (CAD). Differences in transcriptional activity of these cells might reflect the individual's atherosclerotic burden. Transcriptome analysis of circulating mononuclear cells from carefully matched atherosclerotic and control patients will potentially provide insights into the pathophysiology of atherosclerosis and supply biomarkers for diagnostic purposes. From patients undergoing coronary angiography because of anginal symptoms, we carefully matched 18 patients with severe triple-vessel CAD to 13 control patients without signs of CAD on angiography. All patients were on statin and aspirin treatment. RNA from circulating CD4+ T-cells, CD14+ monocytes, lipopolysaccharide-stimulated monocytes, macrophages and CD34+ progenitor cells was subjected to genome-wide expression analysis. Only CD14+ monocytes demonstrated that a small number of genes involved in activation was overexpressed in control patients, which was verified by real-time polymerase-chain reaction. In this pilot study, cautious matching of patients with severe atherosclerotic CAD with control patients without angiographic signs of coronary atherosclerosis did not reveal differences in transcriptional activity in four out of five different mononuclear cell types. In resting monocytes from patients without overt CAD some inflammatory genes were overexpressed as compared to patients with severe CAD. Large inter-individual variability prevented the use of single differentially expressed genes as biomarkers. Keywords: disease-state analysis In total 153 arrays were analyzed with 6 technical replicates (147 biological samples). CD34+ stem cells, CD4+ T-cells, resting CD14+ monocytes, stimulated monocytes and macrophages were analyzed, all from patient with severe coronary atherosclerosis or controls that had no coronary atherosclerosis as determined angiographically, and which were carefully matched for age and gender.

Project description:Objectives: To analyze the gene expression profile of peripheral blood monocytes in different stages of coronary artery disease (CAD) by transcriptome sequencing, and to explore potential genes and pathway involved in CAD pathogenesis. Methods: According to the screening of coronary angiography and quality control of blood samples, 8 intermediate coronary lesion patients were selected, then 8 patients with acute myocardial infarction and 8 patients with normal coronary angiography were matched by age and gender. Transcriptomics sequencing was conducted for the peripheral blood monocytes of these 24 samples by using Illumina HiSeq high-throughput platform. Then differentially expressed genes (DEGs) were analyzed. Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation and protein-protein interaction (PPI) network were applied to annotate the potential functions of DEGs. Results: Compared with the normal coronary angiography group, we identified a total of 169 DEGs in the intermediate coronary lesion group, which were significantly enriched in 59 GO terms and 17 KEGG pathways. Compared with the normal coronary angiography group, we found a total of 2028 DEGs, which were significantly enriched in 311 GO terms and 20 KEGG pathways in the acute myocardial infarction group. The cross-comparison between normal versus intermediate coronary lesion group, and normal versus acute myocardial infarction group included 98 differential genes with 65 up regulated and 33 down regulated genes, which were significantly enriched in 46 GO terms and 10 KEGG pathways. During the progression of CAD, there was a significant up-regulated expression of CSF3、IL-1A、CCR7 and IL-18, and down-regulated expression of MAPK14. Besides GO items such as inflammatory response was significantly enriched, KEGG analysis showed the most remarkable enrichments in IL-17 signaling pathway and cytokine-cytokine receptor interactions. Conclusions: Transcriptomics profiles vary in patients with different severity of CAD. CSF3、IL-1A、CCR7、IL-18 and MAPK14, as well as IL-17 signaling pathway and cytokines and cytokine receptor interaction signaling pathway related with inflammatory response might be the potential biomarker and targets for the treatment of coronary artery disease.

Project description:Rationale: Epicardial adipose tissue (EAT) has been independently associated with non-calcified, high-risk coronary plaques in low-to intermediate risk subjects. Recently, a bidirectional communication was shown between EAT and diseased coronary arteries. In high-risk patients it is unknown whether quantitative measures of EAT can capture, and which molecular players are involved in this mutual interplay. Objective: In a high-risk population, we aimed to determine how the volume of EAT is linked to coronary artery disease (CAD) and to identify potential EAT-deregulated pathways in CAD patients specifically related to coronary artery calcification (CAC). Methods and Results: In a prospective cohort of 574 degenerative severe aortic stenosis patients referred to cardiac surgery, we quantified fat depots by computed tomography (CT) and performed a comparative quantitative proteomics of thoracic fat, including EAT, mediastinal (MAT) and subcutaneous (SAT) adipose tissues. We did not find an independent association of EAT volume with the severity, distribution and complexity of coronary stenosis in invasive coronary angiography. Although, EAT volume was correlated with high CAC, its cardiovascular risk factors-adjusted association was not significant. Taking as reference non-CAD matched-patients and compared to MAT and SAT, EAT proteomic signature of CAD was characterized by up-regulation of pro-calcifying annexins (Annexin A2, ANXA2), fatty acid binding transporters (FABP4) and inflammatory signaling proteins, and by down-regulation of fetuin-A and redox state regulatory enzymes. In EAT, ANXA2 regulation was positively correlated with CAC. EAT gene expression studies confirmed overexpression of ANXA2 and FABP4 in CAD, but no expression of FETUA was detected. Compared with non-CAD, fetuin-A circulating levels were higher in CAD, whereas no fetuin-A pericardial fluid differences were found. Conclusions: In this high-risk cohort, EAT presented an imbalance of pro-calcifying, pro-inflammatory and lipid transporters mediators. These local EAT-mediated regulatory mechanisms were not reflected by the CT volume of EAT alone.

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Circulating Mononuclear Cell Transcriptomes in Patients with Atherosclerotic Coronary Artery Disease

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