| Objectives:Atrial fibrillation(AF)is one of the most common arrhythmia encountered in the clinical practice.In this study,we aimed to identify the molecular biology changes and mechanisms responsible for chronic atrial fibrillation.This study will help to lay the foundation for discovering more safety and effective ways to prevent and treat AF in the future.Methods:100 patients with rheumatic heart diseases who came to TEDA-international cardiovascular hospital,Tianjin,China,for clinical treatment from January 2013 to December 2016 were enrolled in our study.70 patients with chronic atrial fibrillation were assigned to the AF group and 30 patients with sinus rhythm were assigned to the SR group.Isobaric tags for relative and absolute quantification(iTRAQ)technique and gas chromatography-mass spectrometer(GC-MS)technique were performed on the two groups to identify proteins and metabolites.Bioinformatics analysis including Gene Oncology enrichment analysis,KEGG pathway analysis and protein-protein interaction analysis were carried out to identify novel biomarkers and pathways in atrial fibrillation.We then selected 10 proteins for proteomic validation to verify the results of iTRAQ analysis.KEGG pathway analysis were also performed in the GC-MS metabolomic study to help identify possible pathways involved in the atrial fibrillation process.Results:iTRAQ combined with MS techniques identified 27344 peptides or proteins,of which 57 were found to be differentially expressed,i.e.,the proteins fulfilled both the fold change(FC)>1.2 or FC<0.8 and p value=<0.05 criteria.Among the 57 differentially expressed proteins,33 of which were elevated and the remaining 24 proteins were decreased in the AF group.KEGG pathway analysis discovered that peroxisome proliferators-activated receptors(PPAR)pathway,renin angiotensin aldosterone system(RAAS)and coagulation and complement systems were involved in the process of atrial fibrillation.We selected 10 proteins for ELISA validation,including apolipoprotein A-?,apolipoprotein A-?,LIM domain only protein 7,prothrombin fragment 1+2,vitronectin,angiotensinogen,ficolin-3,serum amyloid P-component,macrophage colony-stimulating factor 1 receptor and purine nucleoside phosphorylase.Apolipoprotein A-I(AF:499.5±59.79ug/ml,SR:725.8±83.75ug/ml),LIM domain only protein 7(AF:22.31±1.50pg/ml,SR:16.99±1.88pg/ml),angiotensinogen(AF:208.3±18.29ng/ml,SR:294.1±36.84ng/ml),macrophage colony-stimulating factor 1 receptor(AF:37.76±2.645ng/ml,SR:66.30±10.82ng/ml),prothrombin fragment 1+2(AF:0.97±0.06nmol/ml,SR:0.76±0.05nmol/ml)and vitronectin(AF:53.28±7.20ug/ml,SR:84.89±15.87ug/ml)were found differentially expressed among the two groups by ELISA test.GC-MS metabolomic analysis discovered 322 metabolites and 55 of them were differentially expressed between the AF and SR groups.38 of the metabolites were elevated and 17 of them were decreased.KEGG pathway analysis of the differentially expressed metabolites revealed that galactose metabolism,biosynthesis of unsaturated fatty acids,linoleic acid metabolism,ABC transporters and starch and sucrose metabolism may be related with chronic atrial fibrillation.Conclusions:We for the first time identified the differentially expressed plasma proteins and metabolites in chronic atrial fibrillation patients.Our study suggested that PPAR? pathway,RASS,coagulation and complement systems,galactose metabolism,biosynthesis of unsaturated fatty acids,linoleic acid metabolism,ABC transporters and starch and sucrose metabolism were closely related with atrial fibrillation.Chronic atrial fibrillation may display metabolic remodeling,another form of remodeling other than electrical remodeling and structure remodeling.The utilization of lipids was decreased and the oxidation of glucose was increased in the cardiac tissue.PPAR? pathway is an important cellular pathway modulating the process of energy metabolism and it is of vital importance in the atrial fibrillation metabolic remodeling process. |
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