P1889Quantitative global proteomics and lysine acetylome analysis of changes in left atrial appendage tissue from valvular heart disease patients with atrial fibrillation

Abstract

Abstract Background Previous studies have shown that acetylation plays a critical role in regulating the progress of cardiovascular diseases by acetylated histone and non-histones protein. However, the global lysine acetylome during atrial fibrillation (AF) were not fully understood. Purpose The aim of the present study was to identify the underlying mechanisms of AF via profiling of the quantitative changes of global proteomics and lysine acetylome in the left atrial appendage (LAA) tissues from valvular heart disease patients with AF. Methods This study obtained LAA specimens from patients undergoing cardiac surgery for severe valvular heart disease. The LAA specimens were obtained from both 9 patients with AF and with sinus rhythm (SR). The changes of proteome and acetylome in the AF-LAA vs SR-LAA tissues were studied using dimethyl-labeling, HPLC fractionation, affinity enrichment, LC-MS/MS analysis, database Search and bioinformatic analysis. The acetylated levels of each lysine acetylated site were normalized on the basis of the corresponding protein abundance. Results The bioinformatic analysis indicates 294 up-regulated (AF/SR ratio >1.3) proteins and 169 down-regulated (AF/SR ratio <1/1.3) proteins in the AF-LAA vs SR-LAA were detected. Moreover, 3,880 sites in 1,044 proteins were quantified. Motif analysis of the identified acetylated peptides indicated that a total of 14 significantly enriched amino acid sequence motifs from −10 to +10 surrounding the acetylated lysine (Kac) were defined according to 3412 peptides from 1115 proteins. Among the quantified acetylated sites and proteins, 231 up-regulated acetylated sites in 130 proteins and 121 down-regulated acetylated sites in 74 proteins were detected. The enrichment-based clustering analysis showed that energy metabolism and cardiac contraction-related proteins were highly differentially expressed in the AF-LAA vs SR-LAA. Meanwhile, the protein-protein interaction network of the differentially expressed acetylated proteins demonstrated that there were 146 nodes and 569 interactions in the network and quite a lot of interactions in energy metabolism-related proteins and in cardiac contraction-related proteins. Furthermore, the acetylated levels of most differentially expressed energy metabolism-related proteins involving in oxidative phosphorylation, TCA cycle, respiratory ETC, fatty acid metabolism were up-regulated. On the contrary, the acetylated levels of most acetylated sites in differentially expressed cardiac contraction-related proteins including the key contraction proteins were down-regulated. Interaction network of Ac-proteins Conclusions This study details and expands our understanding of the changes of proteome and lysine acetylome in the LAA tissues from valvular heart disease patients with AF. The data suggest important expression differences of acetylated proteins related to energy metabolism and cardiac contraction which may be involved in the matrix of AF formation and maintainence. Acknowledgement/Funding This work was supported by the grants from the National Natural Science Foundation of China (no. 81600273, no. 81570310, no.81770337 and no.81870258)