Background
Coronary artery disease (CAD) as the most common type of cardiovascular disease, can lead to a complete blockage of blood flowing to the heart, resulting in a heart attack. For its high morbidity and mortality rate, CAD has probably the most serious cardiovascular disorder threatening people’s health, worldwidely [
1].
MicroRNAs (miRNAs) with the length from 18 to 25 nucleotides, is a class of non-protein coding RNA, which has been shown to be involved in a wide variety of biological processes through suppressing the mRNA expression or translation [
2]. MiRNAs have been found to express in various tissues and cell types and play important roles in physiological processes including cell growth, proliferation, differentiation, apoptosis, metabolism, and homeostasis as biological regulators [
3]. MiRNAs were mostly found in body fluids such as blood and the circulating miRNA expression profiles have been shown to differ significantly between healthy and disease including cancers/tumor, diabetes, neurodegenerative diseases, cardiovascular diseases [
3,
4]. So, the blood as one of the most popular non-invasive samples was widely used for identifying potential diagnostic and prognostic biomarkers in human diseases. For CAD, numerous miRNAs have been reported to be circulating biomarkers in the diagnosis of CAD and their functional role in cardiovascular primary prevention has been suggested [
5]. For example, the expression levels of miR-126, miR-17, miR-92a, and the inflammation-associated miR-155 in plasma were significantly reduced in patients with CAD compared with healthy controls. [
6]. The serum miR-197 and miR-223 could be used to predict cardiovascular death in a cohort of patients with symptomatic CAD [
7]. The blood miRNA-19a has been identified as a potential novel biomarker for diagnosis of acute myocardial infarction [
8]. However, the miRNAs identified in a single dataset may be limited.
In our study, using three mRNA microarray data of GSE20680 [
9], GSE20681 [
10] and GSE12288 [
10], as well as three miRNA microarray data of GSE59421 [
11], GSE49823 [
12] and GSE28858 [
13], we aimed to further screen the potential biomarkers related to CAD with different analysis methods.
Discussion
In this study, by using three miRNA microarray and three mRNA microarray of blood samples of CAD and control, a total of 1201 homogenously statistically significant DEGs including 879 up-regulated and 322 down-regulated DEGs and 47 homogenously statistically significant DEmiRNAs including 37 up-regulated and 10 down-regulated DEmiRNAs were identified. Additionally, the WGCNA, miRNA-mRNA regulatory network, functionally enrichment were used to identify the key miRNAs and mRNAs related to CAD. Finally, 5 miRNAs including hsa-miR-361-5p, hsa-miR-139-5p, hsa-miR-146b-5p, hsa-miR-502-5p and hsa-miR-501-5p were identified.
According to the analysis, we found that hsa-miR-146b-5p was significantly up-regulated in the CAD patients. It has been found that miR-146a/b could be involved in CAD by regulating the TLR4 downstream molecules IRAK1 (interleukin-1-receptor-associated kinase 1) and TRAF6 (tumour-necrosis-factor-receptor-associated factor 6) and its level was significantly higher in the CAD group than in the non-CAD group (all
P < 0.01) [
20]. Additionally, miR-146b-5p has also been reported to promote the proliferation, migration and the phenotype transition of vascular smooth muscle cells (VSMCs), which played pivotal roles in vascular remodeling in atherosclerosis [
21]. Dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases [
22]. As a result, has -miR-146b-5p could be the potential factor in CAD.
For hsa-miR-361-5p, it was also significantly up-regulated in the CAD patients. Former study has demonstrated the dysregulation of miR-361-5p/VEGF Axis in the plasma and endothelial progenitor cells of patients with CAD [
23]. LncRNA MEG3-derived miR-361-5p could regulate VSMCs proliferation and apoptosis by targeting ABCA1 [
24]. In the miRNA-mRNA network, hsa-miR-361-5p could regulate the expression of CAV1. The functinal enrichent showed that CAV1 was significantly enriched in the GO term of regulation of cell proliferation. CAV1 which encodes caveolin-1 expressed in cell types relevant to atherosclerosis, was found to be associated with significant risk of CAD when its aberrant expression [
25]. So, CAV1 targeted by hsa-miR-361-5p could involved in the mechanism of CAD through the regulation of VSMCs proliferation.
As for hsa-miR-139-5p, hsa-miR-502-5p and hsa-miR-501-5p, there was no study reporting their directed relationship to CAD. However, it has been found that aberrant expression of hsa-miR-139-5p could lead to apoptosis [
26] which has been observed in coronary atherosclerosis [
27]. hsa-miR-502-5p has been reported to inhibit autophage [
28] and the alteration of autophagic genes has also be discovered in CAD [
29]. So, these three miRNAs could play an important role in CAD.
In our study, we also found that HSF2 was significantly down-regulated in CAD and was the target of both hsa-miR-361-5p and hsa-miR-146b-5p. HSF2, as a heat shock transcription factors, is more prominently activated during mouse heart development [
30]. Former study has demonstrated that HSF2 could induce cardiac hypertrophy during hypertension-induced heart failure by the activation of IGF-IIR [
31]. So, we speculated that HSF2 targeted by hsa-miR-361-5p and miR-146b-5p could be related to CAD.
The study’s limitations should be noted. On the one hand, the methods for screening the biomarkers was based on the statistical method rather than the biological experiment. On the other hand, the miRNA and mRNA data were not from the same project. So the additional experiment such as real-time quantitative PCR was needed to validate the miRNA and mRNA expression levels of the same project.
Conclusions
Above all, we speculated that hsa-miR-361-5p, has-miR-146b-5p, CAV1 and HSF2 could play an important role in CAD. However, further research is required to validate the results.
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