Integrative Multi-omics Approach Reveals the Molecular Characterization and Differences of ECM-PI3K-Akt Pathway among Coronary Artery Bypass Grafting Conduits with Clinical Implications

Abstract

ABSTRACTBACKGROUNDA key problem for results of coronary artery bypass grafting (CABG) is different long-term patency of grafts (internal mammary artery [IMA], radial artery [RA], and saphenous vein [SV]).METHODS AND RESULTSWe investigated the biological differences among IMA-SV, RA-SV, and IMA-RA using multi-omics approaches in order to explore new therapeutic targets. Trios of the human IMA, RA, and SV (n=72) from the CABG patients were studied using transcriptomics and proteomics. Differential mRNAs/proteins were validated by multiple reaction monitoring and real-time quantitative PCR in samples from new cohort of patients. Differentially expressed (DE) RNAs (60 mRNAs, 4 lncRNAs, 2 circRNAs) and 8 proteins in all three comparisons were identified. DE mRNAs and proteins were classified into 4 correlations (non-DE RNAs/non-DEPs, DE RNAs/non-DEPs, non-DE RNAs/DEPs, and DE RNAs/DEPs). Eleven correlated DE mRNAs/DEPs (TSP1, TENA, TENX, VTNC, LAMA4, CO6A3, COMP, ITA1, DAG1, ITA5, and ITA8) were found in ECM-PI3K-Akt pathway, which may play important roles in vasodilation, stenosis, angiogenesis, platelet activation, inflammation, ECM remolding, and atherosclerosis. Importantly, lower TSP1 in IMA or RA than that in SV, lower TENA and LAMA4 in IMA than that in SV or RA, and higher ITA8 in IMA than that in RA may be the reasons of different long-term patency.CONCLUSIONSECM-PI3K-Akt pathway with DE mRNAs and proteins may be the major pathway related to the differences among three grafting vessels. This study provides new insights into the biological differences of the grafts and may form new therapeutic targets for improving the long-term results of CABG.Clinical PerspectiveWhat Is New?We presented a human vessel-specific map on both RNA patterns and protein profiling in three major coronary artery bypass grafting (CABG) grafts: internal mammary artery (IMA), radial artery (RA), and saphenous vein (SV). DE mRNAs and proteins were classified into 4 correlations (non-DE RNAs/non-DEPs, DE RNAs/non-DEPs, non-DE RNAs/DEPs, and DE RNAs/DEPs).We revealed that ECM-PI3K-Akt pathway is the major pathway related to the differences among three major CABG grafting vessels including abundant differentially expressed mRNAs and proteins (TSP1, TENA, TENX, VTNC, LAMA4, CO6A3, COMP, ITA1, DAG1, ITA5, and ITA8).We also revealed that 12 correlated mRNAs and proteins (SUSD5, CO8A1, 3HAO, SRBS2, AIF1L, EFHD1, DESM, TSP1, POSTN, TGM2, HMCN2, and CO6A3) had differences between the arteries and the vein. Five correlated mRNAs and proteins (SUSD2, COCA1, AL1A1, ITA8, and ITIH1) had differences only in IMA-RA.Lower TSP1 in IMA or RA than that in SV, lower TENA and LAMA4 in IMA than that in SV or RA, and higher ITA8 in IMA than that in RA may be the reasons of different long-term patency.What Are the Clinical Implications?This study reveals that the ECM-PI3K-Akt pathway is the major pathway related to the differences among three major CABG grafting vessels including abundant differentially expressed mRNAs and proteins and that the differences in this signaling pathway likely account for the differences in the long-term patency. Therefore, the study provides scientific evidence for why the grafts have different long-term patency at the biological basis in CABG.The study provides new insights into the new therapeutic targets for improving the results of CABG.