Schirmer Stephan H, Fledderus Joost O, van der Laan Anja M, van der Pouw-Kraan Tineke C T M, Moerland Perry D, Volger Oscar L, Baggen Josefien M, Böhm Michael, Piek Jan J, Horrevoets Anton J G, van Royen Niels
Department of Cardiology, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
J Mol Cell Cardiol. 2009 Feb;46(2):177-85. doi: 10.1016/j.yjmcc.2008.10.029. Epub 2008 Nov 14.
Monocytes and T-cells play an important role in the development of atherosclerotic coronary artery disease (CAD). 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 angiographic signs of CAD. All patients were on statin and aspirin treatment. Elevated soluble-ICAM levels demonstrated increased vascular inflammation in atherosclerotic patients. RNA from circulating CD4+ T-cells, CD14+ monocytes, lipopolysaccharide-stimulated monocytes, and macrophages was subjected to genome-wide expression analysis. In CD14+ monocytes, few inflammatory genes were overexpressed in control patients, while atherosclerotic patients showed overexpression of a group of Krüppel-associated box - containing transcription factors involved in negative regulation of gene expression. These differences disappeared upon LPS-stimulation or differentiation towards macrophages. No consistent changes in T cell transcriptomes were detected. Large inter-individual variability prevented the use of single differentially expressed genes as biomarkers, while monocyte gene expression signature predicted patient status with an accuracy of 84%. In this comprehensive analysis of circulating cell transcriptomes in atherosclerotic CAD, cautious patient matching revealed only small differences in transcriptional activity in different mononuclear cell types. Only an indication of a negative feedback to inflammatory gene expression was detected in atherosclerotic patients. Transcriptome differences of circulating cells possibly play less of a role than hitherto thought in the individual patient's susceptibility to atherosclerotic CAD, when appropriately matched for clinical symptoms and medication taken.
单核细胞和T细胞在动脉粥样硬化性冠状动脉疾病（CAD）的发展中起着重要作用。对精心匹配的动脉粥样硬化患者和对照患者的循环单核细胞进行转录组分析，可能会为动脉粥样硬化的病理生理学提供见解，并为诊断目的提供生物标志物。从因心绞痛症状接受冠状动脉造影的患者中，我们精心将18例严重三支血管CAD患者与13例无CAD血管造影迹象的对照患者进行匹配。所有患者均接受他汀类药物和阿司匹林治疗。可溶性ICAM水平升高表明动脉粥样硬化患者的血管炎症增加。对循环CD4 + T细胞、CD14 +单核细胞、脂多糖刺激的单核细胞和巨噬细胞的RNA进行全基因组表达分析。在CD14 +单核细胞中，对照患者中很少有炎症基因过度表达，而动脉粥样硬化患者则显示出一组参与基因表达负调控的含Krüppel相关盒转录因子的过度表达。这些差异在LPS刺激或向巨噬细胞分化后消失。未检测到T细胞转录组的一致变化。个体间的巨大变异性使得无法将单个差异表达基因用作生物标志物，而单核细胞基因表达特征预测患者状态的准确率为84%。在对动脉粥样硬化性CAD中循环细胞转录组的这项综合分析中，谨慎的患者匹配仅揭示了不同单核细胞类型转录活性的微小差异。在动脉粥样硬化患者中仅检测到对炎症基因表达的负反馈迹象。当根据临床症状和所服用药物进行适当匹配时，循环细胞的转录组差异在个体患者对动脉粥样硬化性CAD的易感性中可能发挥的作用比迄今认为的要小。
