Bioinformatics Analysis And Preliminary Validation Of Oxidative Stress-related Genes In Ischemic Cardiomyopathy

Background:Ischemic cardiomyopathy(ICM)is a kind of disease with severe coronary artery stenosis and persistent myocardial ischemia as the basic pathological mechanism,which gradually develops into myocardial fibrosis degeneration and myocardial systolic dysfunction,resulting in cardiac insufficiency.Oxidative stress(OS)refers to a state of imbalance between oxidation and antioxidant action in the body,which is widely considered to be an important factor leading to aging and disease.It has been observed in ischemic cardiomyopathy,but its relationship and the exact mechanism of oxidative stress in ischemic cardiomyopathy remains unclear.Objective:This study uses bioinformatics analysis to screen and validate oxidative stress-related genes in ischemic cardiomyopathy and explore their potential biological functions,providing preliminary evidence based on the transcriptomics of human heart samples to clarify the pathogenesis of ischemic cardiomyopathy and identify potential therapeutic targets and drugs.Methods:(1)Firstly,two large sample datasets of human ischemic cardiomyopathy were screened from the Gene Expression Omnibus(GEO)database.The GSE5406 dataset was used as the discovery dataset to screen for differentially expressed oxidative stress-related gene(DEOSRG)in ischemic cardiomyopathy by bioinformatics,and to perform pathway and functional enrichment analysis.Further,Protein-Protein Interaction Networks(PPI)were constructed to identify key functional modules and hub genes.(2)Next,the GSE79962 dataset was used as a validation dataset to test the diagnostic performance of the pivotal genes and validate their transcriptomic expression levels to identify key genes,and quantitative real-time PCR(q RT-PCR)was used to measure the expression levels of key genes in ICM rat myocardial tissue to further determine their expression changes.(3)Finally,based on the drug relevance data of key genes in the DSig DB database and potential drug candidates for the treatment of ICM were predicted.The binding of protein structures of key genes to the target drugs was further modelled by molecular docking techniques.Result:(1)A total of 32 DEOSRGs were screened in GSE5406 by difference analysis.Functional enrichment analysis showed that these genes were mainly involved in oxidoreductase activity,kinase binding and antioxidant activity,and they were mainly enriched in MAPK signaling pathway,PI3K-AKT signaling pathway,Relaxin signaling pathway and other pathways.After constructing protein-protein interaction(PPI)network,two key modules and eight hub genes were screened out.(2)Five of the eight hub genes(GLRX2,GPX3,HMOX2,PRDX1,PRDX6)in GSE79962 dataset showed significant expression changes with the same trend as in GSE5406 dataset and were identified as key genes.The q RT-PCR results showed that the m RNA expression of key genes in ICM rat myocardial tissue showed a trend of down-regulation compared with the control group,which was consistent with the transcriptome analysis.(3)Based on the five key genes screened from the DSig DB database,Valproic acid(VPA)was identified as a potential therapeutic agent for ICM.Molecular docking simulation showed that the protein structures corresponding to all key genes could bind to valproic acid to form stable complexes.Conclusion:In this study,oxidative stress-related genes were significantly dysregulated in the human ICM cardiac transcriptome.DEOSRGs were mainly located in the Golgi apparatus and endoplasmic reticulum.It mainly involves the response of cells to oxidative stress,chemical stress and oxygen-containing compounds.It mainly affects the activity of oxidoreductase,kinase binding and antioxidant activity.They were mainly involved in MAPK signaling pathway,PI3K-AKT signaling pathway,Relaxin signaling pathway and other pathways.GLRX2,GPX3,HMOX2,PRDX1 and PRDX6 were identified as key oxidative stress-related genes in ischemic cardiomyopathy,and VPA was predicted to be a potential therapeutic agent for ICM.GLRX2 and GPX3 may be potential therapeutic targets for VPA treatment of ICM.This study provides a bioinformatic basis for exploring the biological functions and pathological mechanisms of oxidative stress in ICM.It provides a reference for potential biological targets and therapeutic agents for clinical diagnosis.