肺动脉高压个体中整联蛋白β3靶基因预测及生物信息学分析

Target gene prediction and bioinformatics analysis of integrinβ3 in patients with pulmonary arterial hypertension

目的探究肺动脉高压(PAH)个体中整联蛋白β3促进肺血管重构的分子机制,分析其可能调节的靶基因,为进一步筛选特异的靶向药物提供实验依据。方法从基因表达综合数据库选取GSE33463数据集,微阵列分析特发性PAH患者与健康对照者间差异表达的基因,R语言对测序结果中的基因进行相关性检验,找出与ITGB3具有共表达关系的基因,并进行基因本体论和KEGG富集分析,对ITGB3进行蛋白质相互作用网络分析,获得相对于ITGB3具有统计学意义的基因集合信号转导通路及蛋白与蛋白相互作用关系。小分子药物分析筛选可以调节ITGB3的潜在治疗药物。结果共表达分析结果表明,ITGB3可能与21种基因有关,其中ALAS2与ITGB3呈正相关(相关系数=0.746,P<0.001),CLK1与ITGB3呈负相关(相关系数=-0.613,P<0.001)。基因本体论分析结果表明,ITGB3主要富集的细胞组分为参与细胞黏附的蛋白质复合物和质膜受体复合物等。KEGG通路富集分析结果显示,ITGB3主要参与调控细胞黏着斑通路、磷脂酰肌醇-3-激酶/蛋白激酶B通路、肥厚型心肌病通路和扩张型心肌病通路等。蛋白相互作用网络显示,ITGB3可能与胰岛素样生长因子1(IGF-1)、IGF-1受体(IGF-1R)相互作用,形成ITGB3-IGF-1-IGF-1R复合物,活化下游信号分子。阿地芬宁、马普替林、莫能菌素等小分子药物均是可以调节ITGB3的PAH潜在治疗药物(score分别为-0.878、-0.911、-0.817,均P<0.001)。结论ITGB3可能通过与IGF-1R相结合并促进IGF-1信号通路过度活化,进而促进PAH发展。可依此研究筛选PAH的靶向治疗药物。

Objective To investigate the molecular mechanism of integrinβ3 promoting pulmonary vascular remodeling in patients with pulmonary arterial hypertension(PAH),analyze the possible target genes,and provide an experimental basis for further screening of specific targeted drugs.Methods GSE33463 dataset was selected from Gene Expression Omnibus database,different expressions of genes between patients with idiopathic PAH and healthy controls were analyzed by microarray analysis,and genes from sequencing results were examined for correlation in R language to identify the genes with co-expression relationship with ITGB3,and then analyzed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.The proteinprotein interaction(PPI)network analysis of ITGB3 was analyzed to obtain statistically significant gene sets signal transduction pathways and protein-protein interaction relationships.Small molecule drug analysis screening could modulate potential therapeutic drugs for ITGB3.Results Co-expression analysis showed that ITGB3 might be related to 21 genes,among which ALAS2 was positively correlated with ITGB3(correlation coefficient=0.746,P<0.001),and CLK1 was negatively correlated with ITGB3(correlation coefficient=-0.613,P<0.001).GO analysis showed that the main cellular components enriched by ITGB3 were protein complexes and plasma membrane receptor complexes involved in cell adhesion.KEGG pathway enrichment analysis showed that ITGB3 mainly involved in cell adhesion pathway,phosphatidylinositol 3-kinase/protein kinase B pathway,hypertrophic cardiomyopathy pathway and dilated cardiomyopathy pathway.PPI network showed that ITGB3 might interact with insulin-like growth factor 1(IGF-1)and IGF-1 receptor(IGF-1R)to form ITGB3-IGF-1-IGF-1R complexes that activated downstream signaling molecules.Small molecule drugs such as adiphenine,maprotiline and monensin were potential therapeutic drugs that could regulate ITGB3(score=-0.878,-0.911,-0.817,respectively,all P<0.001).Conclusion ITGB3 may combine with IGF-1R and promote the over-activation of IGF-1 signaling pathway,thereby promoting the development of PAH.The targeted drugs for PAH treatment can select according to that.