Study On The Initiation And Progression Of Coronary Artery Disease By Metabonomics And Transcripnomics Analysis

Objectives:To investigate the metabolic fingerprinting in normal coronary artery subjects,patients with intermediate coronary lesions and acute myocardial infarction.Methods:Metabolic profiles were obtained by ultra-high performance liquid chromatography coupled to quadruple time-of-flight mass spectrometry(Ultra High Performance Liquid Chromatography Coupled to Quadruple Time-Of-Flight Mass Spectrometry,UHPLC-QTOF/MS)to identify the plasma metabolites and altered metabolic pathways in 20 normal subjects(NCA)and different phases of CAD including 19 patients with intermediate coronary lesions(ICL)and 18 AMI patients(AMI)with serious coronary stenosis.Results:554 plasma metabolites were analyzed in all.There were separately 172,26 and 188 differentially expressed metabolic biomarkers in ICL versus NCA group,AMI versus NCA group and AMI versus ICL group.(1)The cross-comparison between ICL versus NCA group and AMI versus NCA group showed that 4 biomarkers were differentially expressed between NCA and CAD groups with different progression periods.Compared with NCA group,L-Alanine,2-Oxoadipic acid,N-Carboxyethyl-gamma-aminobutyric acid and Marmesin were significantly down-regulated in ICL and AMI groups.(2)A total of 131 differential metabolites with non-linear changes were identified between AMI versus ICL group and ICL versus NCA group.Compared with NCA group,L-glutamine and proline were down-regulated in ICL group,but up-regulated between AMI versus ICL group,both with statistically significant difference.During the initiation and progression of CAD the altered metabolic pathways included alanine,aspartate and glutamate metabolism,aminoacyl-tRNA biosynthesis,D-glutamine and D-glutamate metabolism and fatty acid biosynthesis.Conclusions:Different plasma metabolic profiles are detected in the initiation and progression of CAD,L-Alanine and 2-Oxohexanoic acid might be biomarkers for predicting the occurrence of CAD,while L-glutamine and proline are biomarkers strongly associated with the progression of CAD.There are significant changes in the metabolism pathways of alanine,aspartate and glutamate metabolism,aminoacyl-tRNA biosynthesis,D-glutamine and D-glutamate metabolism and fatty acid biosynthesis during the initiation and progression of coronary heart disease.Objective:To analyze the gene expression profile of peripheral blood monocytes in the different stages of coronary artery disease(CAD)by transcriptome sequencing,and to explore potential genes and pathways involved in CAD pathogenesis.Methods:According to the screening of coronary angiography and quality control of blood samples,8 intermediate coronary lesion patients were selected,then 8 patients with acute myocardial infarction and 8 patients with normal coronary angiography were matched by age and gender.Transcriptomics sequencing was conducted in the 24 patients’ peripheral blood monocyte by using Illumina HiSeq high-throughput platform.Then differentially expressed genes(DEGs)were calculated and analyzed.Biological analysis technologies including Gene Ontology(GO)functional annotation,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway annotation and protein-protein interaction(PPI)network were applied to annotate the potential functions of DEGs.Results:Compared with the normal coronary artery group,we identified a total of 169 DEGs in the intermediate coronary lesion group,which were significantly enriched in 59 GO terms and 17 KEGG pathways(gene set 1).Compared with the normal coronary artery group,we found a total of 2028 DEGs,which were significantly enriched in 311 GO terms and 20 KEGG pathways in the acute myocardial infarction group(gene set 2).Compared with the intermediate coronary lesion group,we found a total of 376 DEGs in the acute myocardial infarction group,significantly enriched in 66 GO terms and 20 KEGG pathways(gene set 3).1)During the progression of CAD the cross-comparison genes between gene set 1 and 3 included 4 differential genes:DKK3,NR4A1,HIP1 and PAX8-AS1.2)During the initiation of CAD the cross-comparison between gene set 1 and 2 included 98 differential genes with 65 up regulated and 33 down regulated genes,which were significantly enriched in 46 GO terms and 10 KEGG pathways.During the initiation of CAD,there was a significant up-regulated expression of CSF3、IL-1 A、CCR7 and IL-18,and down-regulated expression of MAPK14.Besides GO items such as inflammation response was significantly enriched,KEGG analysis showed the most remarkable enrichments in IL-17 signaling pathway and cytokine and cytokine receptor interactions.Conclusions:In this study,we preliminarily obtained the differentially transcriptomics profiles of patients with different severity of CAD.We found the changes of DKK3、NR4A1、HIP1 and PAX8-AS1 gene expression may be related to the progression of CAD and the potential correlation between CSF3、IL-1A、CCR7、IL-18、MAPK14 and the initiation of CAD.The DEGs above as well as IL-17 signaling pathway and cytokine and cytokine receptor interaction signaling pathway related with inflammatory response might be the potential biomarker and targets for the treatment of coronary artery disease.Cardiovascular disease(CVD)has the highest morbidity and mortality in the world,meanwhile CAD is the leading cause of death in CVD.At present,some studies have explored the pathogenesis,progression and prognosis risk of CAD by detecting novel biomarkers through multi-omics technologies.Omics biomarkers(such as genomics,epigenomics,transcriptomics,metabonomics and proteomics)offer the opportunity to obtain the informations that underlies disease,which has potential effect on risk assessment and prognostication of CAD.However,far more evidence is needed at present.This review summarizes the information,technology and clinical data of novel omics biomarkers related to CAD.In the future,the integrated application of multi-omics technology is expected to find more novel CAD markers and better control the initiation and progression of CAD.