Role of PPAR Pathway in Atrial Fibrillation Associated with Heart Valvular Disease: Transcriptomics and Proteomics in the Human Atrial Tissue

Abstract

ObjectiveAtrial fibrillation (AF) is one of the most common cardiac arrhythmias. Previous studies have shown that electrical, contractile, and structural remodeling play the key role in the onset and maintenance of AF. Heart valvular disease (HVD) is associated with an increased risk of thromboembolic events, mainly in patients with AF. However, the molecular mechanism of AF in HVD remains unrevealed, although there was an attempt to discover the plasma biomarkers in HVD.MethodsHuman atrial tissues from patients with HVD in persistent AF preoperatively for at least 6 months or remaining sinus rhythm (as control) undergoing heart valve replacement surgery were studied by combined transcriptomics and proteomics. Owing to the fact that there are maximal 8 Isobaric tags in proteomics analysis by iTRAQ technology, 8 tissue samples were allocated, including left atrial tissues from 3 AF patients (AFLA) and right atrial tissues (3 AFRA and 2 SRRA) from 5 patients. The analysis of transcriptomics and proteomics were from the same samples. Big data obtained from omics study were analyzed by bioinformatics tools. The fold changes of >1.2 (or <0.8) and P value < 0.05 were considered as significant.ResultHierarchical clustering analysis revealed that the genomic expressions of three groups have differences in transcriptomics. Pairwise comparison was performed and differentially expressed genes were identified, including 193 genes up‐regulated and 279 genes down‐regulated. Heat map from differentially expressed proteins in proteomics analysis indicates that there are significant differences in patients with or without AF and between the left and right atrium. Based on Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we found that the expression of genes and proteins associated with PPARα, β/δ, γ was altered in omics study in AF patients. Genes/proteins, such as FATCD36, SCD‐1, FABP, ADIPO, APOA1, APOA2, FATP, FADS2, ACBP, CPT‐1, aP2, CAP, and etc., are included in the PPAR pathway. These genes/proteins may be developed as potential biomarkers for disease pathogenesis and progress in AF.ConclusionOur study provides an integrative analysis of transcriptomics and proteomics in human atrial tissues of AF‐associated HVD patients and reveals that PPAR signaling pathway plays an important role in pathogenesis of AF. Some of differential proteins may become biomarkers and provide new diagnostic and therapeutic methods for AF in the future.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China [81870288 & 81870227]; the Non‐profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019XK310001& 2018TX31002]; Tianjin Science and Technology Committee[18PTZWHZ00060];Binhai New Area Health Bureau (2018BWKZ005)