| Background:Diabetic cardiomyopathy(DCM)is a kind of diabetes-related cardiovascular complication,which is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors,such as hypertension,coronary heart disease and valvular heart disease.Myocardial damage and hypertrophy induced by high glucose is the main pathophysiological processes of most DCM.However,the mechanism of cardiomyocyte injury induced by high glucose has not been fully elucidated.Immnue infitration is a biological process closely related to the cardic injury of DCM,and it also has a tight relationship with hyperglycemia-induced myocardial damage.In this study,in order to improve the clinical treatment efficacy and safety of DCM,we screened key genes involved in DCM,analyzed the relationship between key genes and immune infiltration,and further identified the potential drugs for treatment of DCM.Objective:The purpose of this study is to screen the key genes in high glucose-induced myocardial damage by bioinformatics analysis and to screen targeted drugs.Methods:(1)The module genes in hyperglycemia-induced myocardial damage were identified by weighted co-expression network analysis(WGCNA).(2)The module genes and differentially expressed genes in hyperglycemia-induced myocardial damage were integrated for functional annotation and pathway enrichment analysis.The top 10 key genes(Hub genes)were obtained by constructing the protein-protein interaction(PPI)network.(3)The correlation between Hub gene and immune infiltration was analyzed by CIBERSORT(4)CTD database was searched to identify pharmacological compounds targeting Hub genes.The molecular docking simulation of proteins encoded by the hub gene with small molecule drugs was performed.Results:(1)In turquoise(4021),black(200)and yellow(279)modules,4500 genes were significantly correlated with hyperglycemia-induced myocardial damage.(2)A total of 1127 genes were significantly differentially expressed in hyperglycemia group,among which 680 genes were also included in key module genes.The GO analysis of intersection genes showed enrichement in celluar component such as collagen-containing extracellular matrix,cell-cell junction,cell-substrate junction and focal adhesion,molecular function such as actin binding,carbohydrate binding,extracellular matrix structural constituent,and sulfur compound binding,and biological processes such as cell-substrate adhesion,response to hypoxia,extracellular matrix organization,and cholesterol metabolic process etc.KEGG analysis showed intersection genes were mainly enriched in HIF-1 signaling pathway,DNA replication,Terpenoid backbone biosynthesis,mismatch repair.Gene Set Variation Analysis(GSVA)indicated that the top 10 enriched downregulated pathways in high glucose group were: reaction deposition of new cenpa containing nucleosomes at the centromere,reactome nuclear signaling by Erbb4,reactome inwardly rectifying K channels,WP oxysterol derived from cholesterol,WP mevalonate pathway,WP cholesterol biosynthesis pathway,KEGG steroids biosynthesis,reactome metabolism of steroids,PID Tap63 pathway;The top 10 enriched up-regulated pathways in high glucose group were: WP computational model of berobic glycolysis,WP photodynamic therapy induced HIF-1 survival signaling,WP hereditary leiomyomatosis and renal cell carcinoma pathway,KEGG adipokine signaling pathway,reactome laminin interactions,reactome platetet adhedion to exposed collagen,reactome assembly of collagen fibrils and other multimeric structures,PID TCPTP pathway,reactome crosslinking of collagen fibrils,reactome scavenging by class B receptors.There were 1005 interacting pairs and 353 nodes in the PPI network.The top 10 hub genes were PCNA,FEN1,ESR1,PTPN11,CAV1,GAPDH,CASP3,ITGA1,PXN and ACTN2 respectively.(3)As indicated by the immune infiltration,CASP3 was positively correlated with Tregs.PCNA was negatively correlated with γδT Cell.PXN was negatively correlated with Neutrophils.Resting mast cells and activated dendritic cells,ACTN2 and ITGA1 were negatively correlated with naive B cells.and PXN was negatively correlated with Neutrophils,resting mast cells and activated dendritic cells.(4)The drugs targeting PCNA、FEN1、ESR1、PTPN11、CAV1、GAPDH、CASP3、ITGA1、PXN and ACTN2 were bisphenol A,Acetaminophen,Estradiol,Tretinoin,Valproic Acid,bisphenol A,Resveratrol,Valproic Acid,Acetaminophen and Cocaine,respectively.Conclusion:(1)A total of 680 key module genes were found between high glucose and control samples,which were mainly enriched in collagen-containing extracellular matrix,cell-cell junction,cell-substrate junction and focal adhesion,and closely related to HIF-1 signaling pathway,DNA replication,terpenoid backbone biosynthesis,mismatch repair pathway.(2)PCNA,FEN1,ESR1,PTPN11,CAV1,GAPDH,CASP3,ITGA1,PXN and ACTN2 were closely associated with the occurrence and development of hyperglycemia-induced myocardial damage,and might serve as the potential target for the treatment of DCM.(3)Bisphenol A,Acetaminophen,Estradiol,Tretinoin,Valproic Acid,Resveratrol,and Cocaine were the potential drugs targeting the hub genes for diabetic cardiomyopathy. |
