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

BACKGROUND A 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]).

AND RESULTS We 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.

ECM-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 Perspective What 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by grants from the National Natural Science Foundation of China [82170353 & 82370350]; Tianjin Science and Technology Commission [22ZYQYSY00020 & 21JCYBJC01120]; the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2020-PT310-007 & 2019XK310001], and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-019A). Tianjin Municipal Heath Commission [TJWJ2023MS054] Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by the Ethics Committee of the TEDA International Cardiovascular Hospital ([2019]-0826-4). Informed consent was obtained before surgery. All samples were collected according to the principles outlined in the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability The data underlying this article will be shared on reasonable request to the corresponding author. Nonstandard Abbreviations and Acronyms - CABG - coronary artery bypass grafting - cGMP - cyclic guanosine monophosphate - DE - differentially expressed - DEPs - differentially expressed proteins - eNOS - endothelial nitric oxide synthase - FPKM - Fragments Per Kilobase Million - GO - Gene Ontology - IMA - internal mammary artery - KEGG - Kyoto Encyclopedia of Genes and Genomes - MRM - Multiple Reaction Monitoring - NO - nitric oxide - RA - radial artery - SV - saphenous vein