左心室辅助装置对心肌病心肌转录组影响

Effect of left ventricular assist device on myocardial transcriptome of cardiomyopathy

目的探讨左心室辅助装置(LVAD)对终末期心肌病患者心肌基因表达谱改变及其生物学意义。方法从GEO数据库(http://www.ncbi.nlm.nih.gov/geo)检索并筛选植入LVAD的终末期射血分数降低型心力衰竭患者心肌mRNA表达谱数据集。用韦恩图分析工具筛选目标数据集的共有差异表达基因(DEG)。选择来自至少2个数据集的DEG进入后续分析。用GEO2R筛选DEG,用GSE52601验证DEG。对DEG进行基因本体论(GO)、京都基因与基因组百科全书(KEGG)和基因集富集分析(GSEA),用STRING和Cytoscape构建蛋白-蛋白互作网络,识别核心模块和枢纽基因。结果共检索出4个目标数据集GSE430、GSE974、GSE21610、GSE52601。前3个作为训练集;GSE52601为验证集,对筛选出的核心DEG进行验证。共鉴定33个DEG(22个下调、11个上调),与中性粒细胞脱颗粒和G蛋白偶连受体配体结合相关;筛选出一个由15个枢纽基因组成的核心模块,与对炎症损伤的响应及调控、趋化因子经G蛋白偶联受体介导的信号转导相关,涉及丝裂原活化蛋白(MAP)/细胞外信号调节激酶(ERK)、肌动蛋白丝、γ-氨基丁酸β(GABA-B)受体、唾液酸、前列蛋白E受体、CD40受体和白细胞介素8受体等通路,尿激酶型纤溶酶原激活剂基因(PLAU)和CD163分子基因(CD163)在验证集中呈现相同变化趋势。结论LVAD对心肌病理重构的分子机制与趋化因子经G蛋白偶联受体介导的炎症通路相关,为选择合适的LVAD类型和评估LVAD治疗效果提供了基因水平的依据。

Objective To investigate the effect of left ventricular assist device(LVAD)on myocardial gene expression profile in patients with end-stage cardiomyopathy and its biological significance.Methods Myocardial mRNA expression profile data set of patients with end-stage heart failure with reduced ejection fraction implanted with LVAD was retrieved and screened from the GEO database(http://www.ncbi.nlm.nih.gov/geo).The common differentially expressed genes(DEG)of target data set were screened by Venn diagram,and DEG from at least two data sets were selected for subsequent analysis.The DEG was screened by GEO2R and verified by GSE52601.Gene ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)and gene set enrichment analysis(GSEA)were performed on DEG.STRING and Cytoscape were used to construct protein-protein interaction networks to identify core modules and hubgenes.Results A total of 4 target data sets GSE430,GSE974,GSE21610 and GSE52601 were retrieved.The GSE430,GSE974,GSE21610 were used as training sets and GSE52601 as verification set to verify the selected core DEG.A total of 33 DEG(22 down-regulated and 11 up-regulated)were identified,which were related to neutrophil degranulation and G protein-coupled receptor ligand binding.A core module composed of 15 hub genes was screened out,which was related to the response and regulation of inflammatory injury and chemokine signal transduction mediated by G protein-coupled receptors,and involved in pathways such as mitogen-activated protein(MAP)/extracellular signal-regulated kinase(ERK),actin filament,gamma-aminobutyric acidβ(GABA-B)receptor,sialic acid,prostaglandin E receptor,CD40 receptor and interleukin-8 receptor.Plasminogen activator urokinase gene(PLAU)and CD163 molecular genes showed the same trend in validation set.Conclusion It is demonstrated that molecular mechanism of LVAD on myocardial pathological remodeling is related to inflammatory pathway mediated by G protein-coupled receptor,which provides genetic basis for selecting appropriate type of LVAD and evaluating therapeutic effect of LVAD.