Atherosclerotic disease and its thrombotic complication may lead to the development of CHD, and if untreated, it progresses into myocardial infarction. Exosomes are a type of extracellular vesicle that contain constituents (protein, DNA, and RNA) of the cells that secrete them .
Despite years of research, the underlying pathogenesis of coronary artery disease has not been fully defined. Recently, dysregulated expression of RNAs (lncRNAs, circRNAs, miRNAs, mRNAs) have been partially found to be associated with CHD [8, 23]. However, serum RNAs might often be degraded by RNA enzyme and may not accurately reflect the pathological differences. While exosomes could protect them from being degraded . Hence, we identified serum exosomal-associated RNAs and constructed the ceRNA network in CHD, revealing a new targeting axis in the pathogenesis of CHD. To our knowledge, this was the first to explore exosomal-associated ceRNA network in CHD.
In this study, we first identified 312 DEMs, 85 DECs and 43 DELs involving in the pathogenesis of coronary heart disease. Enrichment analysis and PPI network were subsequently performed, of which, UBC (ubiquitin C) was one of the most important hub genes. After the prediction of miRNAs targeting mRNA, exosomal-associated circRNA/lncRNA-miRNA-mRNA ceRNA network was constructed. Our results suggest specific ceRNA axes in the pathogenesis of CHD, which may be promising targets for CHD diagnosis.
UBC (Ubiquitin C), belonging to the ubiquitin family, is associated with protein degradation, DNA repair, kinase modification, autophagy, regulation of inflammation and regulation of other cell signaling pathways [24, 25]. Our enrichment analysis both in DEMs and hub genes showed UBC participated in cellular protein metabolic process. Ji Y and his colleagues  proved that the expression level of ubiquitin was significantly higher in CHD patients than healthy individuals and the levels of ubiquitin were consistent with the severity of different classes of CHD. Our study further confirmed the function of UBC in the pathogenesis of CHD, which could be a non-invasive biomarker.
MiR-17-5p was reported to regulate cell cycle, proliferation, apoptosis. Board evidence has elucidated its profound function in regulating cardiovascular diseases. The deficiency of miR17 in neonatal mice is lethal and the over-expression of miR-17-5p could extend the life span of mice . Liu G et al  confirmed the up-regulation of miR-17-5p could contribute to hypoxia-induced proliferation of human pulmonary artery smooth muscle cells, leading to pulmonary hypertension. Yang S et al  found miR-17-5p silencing protects heart function after AMI through decreasing the rate of apoptosis and repairing vascular injury. Moreover, recent studies have shown circulating miR-17-5p could be a novel biomarker for diagnosis of acute myocardial infarction .
MiR-20b-5p was found to attenuate hypoxia-induced apoptosis in cardiomyocytes . Also, Zhen W et al  found the overexpression of miR-20b-5p could increase cell viability and repress autophagy and apoptosis in human umbilical vein endothelial cells with hypoxia-reoxygenation injury. Both hypoxia and hypoxia-reoxygenation models are similar to patients with MI and revascularization of MI, we considered its vital role in regulating CHD. However, there has been little research about the function of miR-20b-5p in CHD patients, which needs to be further validated.
The lncRNA RPL7AP11 (ribosomal protein L7a pseudogene 11) is a pseudogene of ribosomal protein L7a (RPL7A). Lou W et al  found RPL7A was down-regulated in high density lipoprotein induced vascular endothelial cell line ECV 304. Pseudogenes, abundant in the human genome, were considered as non-functional "junk genes traditionally . Recent studies have proved its function in various diseases. However, there has been limited research on RPL7AP11. More evidence needs to be confirmed.
Our study demonstrated that RPL7AP11 could sponge hsa-miR-17-5p and hsa-miR-20b-5p to upregulate UBC, thus regulating the pathogenesis of CHD through cellular protein metabolic process.
There are some limitations to the present study. Firstly, the sample scale was not large. An additional validation cohort should be included in further studies to analyze the expression of these identified lncRNAs, circRNAs, miRNAs and mRNAs. Secondly, how these novel exosomal-associated ceRNA axes participate in the process of CHD development is still unclear. Further cell and animal experiments are needed to verify these findings.