尼古丁影响糖尿病心肌病进展的机制研究

The Mechanism of Nicotine Influence on Diabetic Cardiomyopathy

目的基于生物信息学技术深度挖掘人糖尿病心肌病相关数据库,揭示尼古丁对糖尿病心肌病(DCM)的作用靶点进而阐明其相关机制。方法通过3大数据库(GEO数据库、Drug bank数据库、STRING数据库)和WGCNA分析对DCM和尼古丁的相关基因进行筛选,揭示尼古丁影响DCM的潜在的hub基因,基于hub基因本体(GO)分析和基因组百科全书(KEGG)分析,通过Cytoscape软件构建影响DCM的hub基因网络以及关键靶点相关通路的交互图,进一步对hub基因和疾病调控基因进行相关性分析,鉴定hub基因与免疫浸润的关系,最后构建hub基因参与的miRNA-mRNA共表达网络,预测hub基因的转录因子,同时ROC曲线探讨靶点与DCM发生发展的关系。结果共筛选出630个差异基因,共2个hub基因:神经元乙酰胆碱受体β4亚基(Chrnb4)、细胞色素酶P4501A1(Cyp1a1),其主要参与Fe^(3+)反应、维甲酸生物合成过程和影响色氨酸代谢、卵巢类固醇生成;尼古丁通过hub基因加重DCM心肌病进程主要与免疫细胞含量显著相关,此调节过程涉及35个miRNA,2个mRNA,Cyp1a1转录因子;ROC曲线显示Chrnb4(AUC:0.707)、Cypla1(AUC:0.769)可作为DCM心肌病的诊断指标。结论尼古丁可加重DCM心肌病的进程,其与Chrnb4、Cyp1a1相关并通过miRNA-RNA互作调节免疫细胞含量,从而可为治疗吸烟人群中DCM患者心脏的损伤情况提供新的思路。

Objective To explore the related database of human diabetic cardiomyopathy based on bioinformatics technology,reveal the target of nicotine on diabetic cardiomyopathy(DCM)and elucidate its related mechanism.Methods The related genes of DCM and nicotine were screened by three major databases(GEO database,Drug bank database,STRING database)and WGCNA analysis,and the potential hub genes of nicotine affecting DCM were revealed.Based on hub gene ontology(GO)analysis and genome encyclopedia(KEGG)analysis,the interaction diagram of hub gene network and key target related pathways affecting DCM was constructed by Cytoscape software,and the correlation between hub genes and disease regulatory genes was further analyzed to identify the relationship between hub genes and immune infiltration.Finally,a miRNA-mRNA co-expression network involving hub genes was constructed to predict the transcription factors of hub genes,and the ROC curve was used to explore the relationship between the target and the occurrence and development of DCM.Results A total of 630 differential genes were screened out,including two hub genes:neuronal acetylcholine receptorβ4 subunit(Chrnb4)and cytochrome P4501A1(Cyp1a1),which were mainly involved in Fe^(3+) reaction,retinoic acid biosynthesis,tryptophan metabolism and ovarian steroid production.The process of nicotine aggravating DCM cardiomyopathy through hub gene was mainly related to the content of immune cells,which was involved 35 miRNAs,2 mRNAs,Cyp1a1 transcription factor;ROC curve showed that Chrnb4(AUC:0.707)and Cypla1(AUC:0.769)could be used as diagnostic indicators for DCM cardiomyopathy.Conclusion Nicotine can aggravate the process of DCM cardiomyopathy,which is related to Chrnb4 and Cyp1a1 and regulates the content of immune cells through miRNA-RNA interaction,thus providing a new idea for the treatment of cardiac injury in DCM patients in smoking population.