ReviewPotential roles of microRNAs and long noncoding RNAs as diagnostic, prognostic and therapeutic biomarkers in coronary artery disease
Introduction
Coronary artery disease (CAD), which is still a major health challenge, contributes to significant morbidity and mortality and imposes a major socioeconomic burden worldwide [1,2]. In 2020, approximately 11.1 million patients died due to CAD-related complications [3], suggesting that the need for drugs with novel targets and for biomarkers ideally appropriate for identifying and detecting CAD much earlier, which can provide prompt diagnosis of this disease and may facilitate the treatment [4,5]. It is noted that conventional diagnostic and prognostic biomarkers are already available that could detect and predict heart diseases, for example, the highly sensitive troponins, NT-proBNP, the Systematic Coronary Risk Evaluation and the left ventricular ejection fraction, which could predict the risk which were associated with severe heart disease for nearly a decade [6]. However, these methods are effective only in the prevention of primary CAD and rarely provide reliable results that applied to patients who already have heart-related disease. Currently, the next-generation sequencing (NGS) is considered as “the gold standard” highly reliable technique for the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) identification and is widely used for whole genome sequencing, investigation of genome diversity, metagenomics, epigenetics, discovery of non-coding RNAs and protein-binding sites. The deep RNA-sequencing using NGS can detect both known and novel transcripts, and it was adopted to detect CAD in the plasma. Zoe et al. identified fragments from 3986 messenger RNAs, 164 long non-coding RNAs, 405 putative novel lncRNAs and 227 circular RNAs in plasma by RNA-sequencing [7]. And this technology was also adopted in myocardial infarction, Zhang et al. revealed that 60 coding genes were detectable and thus tested in an independent RNA-seq data of 807 individuals [8]. Wang et al. found that lncRNA Mirt1 was a critical regulatory factor in the chronic intermittent hypoxia exaggerated post-myocardial infarction remodelling via RNA-seq data [9].
It is known that the progression and incidence of CAD are closely related to the function of noncoding RNAs (ncRNAs), which includes miRNAs, small interfering RNAs (siRNAs), and lncRNAs [10]. MiRNAs dysregulation has been identified in different CAD types, revealing that those transcripts can serve as biomarkers under this devastating condition [11]. Furthermore, miRNAs have been identified to regulate gene expression at the posttranscriptional levels by inhibiting gene translation, promoting mRNA degradation or blocking mRNA translation [[12], [13], [14]]. In the heart, miRNAs have been confirmed to participate in the cardiovascular development, fibrosis, and hypertrophy modulation [[15], [16], [17]]. LncRNAs, also called large ncRNAs, are noncoding RNA transcripts with a length of >200 nucleotides, which are mainly generated from transcriptional units to resemble protein-coding genes or influence genomic organization [[18], [19], [20]]. LncRNAs play significant roles in fundamental processes during gene, like transcriptional regulation and chromatin modification [21]. Many studies have been carried out on the relationships of miRNAs and lncRNAs with human diseases such as breast cancer, inflammatory disorders, glioma, and HBV infection [[22], [23], [24], [25]]. Previous studies have summarized views or details on molecular pathomechanisms and targets in the noncoding genome. Since miRNA and lncRNA biomarkers have been well studied from the perspective of aberrant molecular pathways, they are also considered crucial for the identification of patients who are likely to benefit from specific molecular therapy. Application of these biomarkers in clinical practice is significant to help clinicians detect diseases in a timely and precise manner. Herein, we review current publications to discuss the potential utility of miRNAs and lncRNAs that serve as novel diagnostic, prognostic, and therapeutic biomarkers for clinical application of CAD.
Section snippets
CAD biomarkers
Commonly, cardiac troponins are used as indicators for adverse cardiac events [26], and creatine kinase is also adopted, although it exhibited less specific because of its presence in cerebral tissue and skeletal muscle. However, biomarker molecules are found to be involved in the terminal series of events in CAD, such as ischaemic damage to the myocardium arising due to acute coronary syndrome [27]. Furthermore, a wide array of other biomarkers, C-reactive protein, and genetic polymorphism
MicroRNAs involved in different CAD related processes
Unlike these biomarkers, miRNAs can distinguish between individuals with different cardiovascular health statuses [[33], [34], [35], [36]]. Those miRNAs can be measured at some local sites, like sites of plaques or endothelial injury, or freely circulating in serum. miRNAs have been well studied and explored as clinical biomarkers in numerous previous studies [37]. Studies have evaluated miRNAs as biomarkers in CAD and acute myocardial infarction (AMI) by comparing them with established
miRNAs as diagnostic biomarkers in CAD
The miRNAs found in the circulation of CAD patients potentiates their usage as diagnostic biomarkers. Han et al. indicated that up-regulated expression of miR-34a, miR-21, and miR-23a were detected in the plasma of 32 patients with CAD, therefore might function as diagnostic biomarkers of CAD progression [65]. Julien et al. carried out a cross-sectional study in 69 patients with CAD and revealed that the expression of let-7c, miR-155, and miR-145 was significantly declined compared with that in
LncRNAs involved in different CAD related processes
LncRNAs refer to noncoding RNA transcripts that are longer than 200 nt, which are derived from transcriptional units but lack coding potential. These transcriptional units were initially found to represent only bystander transcription especially in protein-coding regions. However, evidence has suggested that lncRNAs may contribute to biological processes, including transcriptional and translational modulation, cell signalling, chromatin modification, and human disease [[80], [81], [82]]. In
LncRNAs as diagnostic biomarkers in CAD
Yao et al. showed that receiver operating characteristic disclosed that ANRIL could distinguish CAD patients from controls with an area under the curve of 0.789 (95%CI: 0.731–0.847), suggesting that ANRIL presented a good diagnostic value for CAD [88]. Yin et al. found that the expression level of GAS5 was significantly lower in patients with CAD when compared to patients with diabetes mellitus, the following ROC curve analysis showed that GAS5 may serve as a promising biomarker for CAD [92].
MiRNA–lncRNA interactions in CAD
miRNAs can regulate the transcription of lncRNAs, while the effects of this regulation might in turn lead to blockade of miRNA-related effects via the intrinsic sponging activity of lncRNAs. Whereas the mechanistic roles of miRNAs and lncRNAs have been described above, the potential of those transcripts to serve as new biomarkers appear intriguing in CAD, particularly due to their altered expression levels observe in CAD different stages.
miRNA can trigger the decay of lncRNAs. For example, the
Challenges of miRNAs and lncRNAs as biomarkers in CAD
The field of miRNA and lncRNA biomarker research, as well as their potential clinical applications is rapidly progressing. To date, numerous publications have revealed the pathogenetic, diagnostic, prognostic and therapeutic value of miRNAs and lncRNAs in CAD. The functional mechanisms of miRNAs and lncRNAs in the pathogenesis of CAD are shown in Fig. 1. Despite the many reasons for enthusiasm about the use of miRNAs and lncRNAs as novel molecular biomarker targets for the treatment of CAD, the
Conclusions
In this review, we have addressed the current understanding of the biogenesis and pathophysiological roles of miRNAs and lncRNAs in CAD and discussed perspectives on their potential future use as promising diagnostic, prognostic and therapeutic biomarkers, for cardiovascular diseases. MiRNAs can regulate CAD development through different pathways and mechanisms, including modulation of VSMC activity (miR-18-5p [135], miR-32 [136], miR-574-5p [137]), inflammatory responses (miR-146a [138],
Funding
This work was supported by the Science and Technology Program of Education Department of Jilin Province (No. JJKH20230543KJ, No. JJKH20180828KJ), Jilin Province College students Innovation Training Project (No. 202013706037, No. S202213706028), Natural Science Fund Program of Science and Technology Department of Jilin Province (No. 20180101105JC), the Health Commission Project of Jilin Province (No. 2020Z006).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
YJ, FF, JC designed and conceived the manuscript, YJ and YZ wrote the manuscript draft. ZL and SC interpreted the data. FF and YJ revised the manuscript. JC provided many comments. All authors contributed to the article and approved the submitted version.
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