Quantitative proteomics profiling of lysine 2‐hydroxyisobutyrylation in right atrial appendage from rheumatic heart valve disease patients

Abstract

ObjectivesLysine 2‐hydroxyisobutyrylation (Khib) is a novel acylation that regulates glycolysis. Little has been done in human diseases regarding the role of Khib. The present study was designed to reveal the role of Khib in the development of atrial fibrillation (AF) associated with heart valve disease.MethodsDiscarded right atrial appendage tissues during the cannulation procedure were collected from AF and sinus rhythm (SR) patients with rheumatic heart valve disease. The protein profiles and Khib sites were identified and qualified by Tandem Mass Tag labeling and liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) technology. Bioinformatic tools, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein‐protein interaction, were also used to explore the biological function between AF and SR.ResultsA total of 6,523 matched spectrum, 3,234 peptides, 2,867 modified peptides, corresponding to 579 proteins and 2,900 sites from LC‐MS/MS analysis were identified. Of these identified proteins and sites, 480 proteins and 2,275 sites were quantifiable. The length of most peptides distributed between 7 and 22, which was consistent with the length of tryptic peptides. Differentially expressed Khib sites analysis showed that there were 35 and 48 Khib sites related to 124 and 67 proteins exhibited upregulation and downregulation in AF compared to SR. Subcellular location analysis of Khib ‐related proteins revealed that cytoplasm, nucleus, and extracellular accounted for the most proportion. Bioinformatic analysis demonstrated that proteins with Khib were significantly enriched in different biological approach, such as cysteine and methionine metabolism, cGMP‐PKG signaling pathway, and glucose‐responsive energy metabolism.ConclusionsThe present study for the first time revealed larger number of differentially expressed Khib sites between AF and SR in patients with rheumatic valve disease. The proteins related to these sites are involved in diverse cellular processes including energy metabolism. These results indicate that Khib modification might be a key factor in occurrence of AF in patients with rheumatic heart valve disease.