Review
Potential roles of microRNAs and long noncoding RNAs as diagnostic, prognostic and therapeutic biomarkers in coronary artery disease

https://doi.org/10.1016/j.ijcard.2023.03.067Get rights and content

Highlights

  • MicroRNAs are involved in different CAD related processes.

  • miRNAs as diagnostic, prognostic and therapeutic biomarkers in CAD.

  • LncRNAs are involved in different CAD related processes.

  • LncRNAs as diagnostic, prognostic and therapeutic biomarkers in CAD.

Abstract

Coronary artery disease (CAD), which is mainly caused by atherosclerotic processes in coronary arteries, became a significant health issue. MicroRNAs (miRNAs), and long noncoding RNAs (lncRNAs), have been shown to be stable in plasma and could thereby be adopted as biomarkers for CAD diagnosis and treatment. MiRNAs can regulate CAD development through different pathways and mechanisms, including modulation of vascular smooth muscle cell (VSMC) activity, inflammatory responses, myocardial injury, angiogenesis, and leukocyte adhesion. Similarly, previous studies have indicated that the causal effects of lncRNAs in CAD pathogenesis and their utility in CAD diagnosis and treatment, has been found to lead to cell cycle transition, proliferation dysregulation, and migration in favour of CAD development. Differential expression of miRNAs and lncRNAs in CAD patients has been identified and served as diagnostic, prognostic and therapeutic biomarkers for the assessment of CAD patients. Thus, in the current review, we summarize the functions of miRNAs and lncRNAs, which aimed to identify novel targets for the CAD diagnosis, prognosis, and treatment.

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.

References (147)

  • S. Komal et al.

    MicroRNAs: emerging biomarkers for atrial fibrillation

    J. Cardiol.

    (2019)
  • X. Sun et al.

    Exploring the regulatory roles of circular RNAs in the pathogenesis of atherosclerosis

    Vasc. Pharmacol.

    (2021)
  • Q. Cao et al.

    Circular RNAs in the pathogenesis of atherosclerosis

    Life Sci.

    (2020)
  • S. Kalayinia et al.

    MicroRNAs: roles in cardiovascular development and disease

    Cardiovasc. Pathol.

    (2021)
  • F. Olivieri et al.

    Diagnostic potential of circulating miR-499-5p in elderly patients with acute non ST-elevation myocardial infarction

    Int. J. Cardiol.

    (2013)
  • Y.H. Zhang et al.

    Effects of MicroRNA-499 on the inflammatory damage of endothelial cells during coronary artery disease via the targeting of PDCD4 through the NF-Kappabeta/TNF-alpha signaling pathway

    Cell. Physiol. Biochem.

    (2017)
  • C. Xiao et al.

    MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb

    Cell.

    (2016)
  • Y. Zhang et al.

    Secreted monocytic miR-150 enhances targeted endothelial cell migration

    Mol. Cell

    (2010)
  • E. Raitoharju et al.

    miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere vascular study

    Atherosclerosis.

    (2011)
  • Y. Liu et al.

    Atherosclerotic conditions promote the packaging of functional MicroRNA-92a-3p into endothelial microvesicles

    Circ. Res.

    (2019)
  • Z. Yin et al.

    A key GWAS-identified genetic variant contributes to hyperlipidemia by upregulating miR-320a

    iScience.

    (2020)
  • H.M. Li et al.

    Angiogenic and antiangiogenic mechanisms of high density lipoprotein from healthy subjects and coronary artery diseases patients

    Redox Biol.

    (2020)
  • S. Hou et al.

    MicroRNA-939 governs vascular integrity and angiogenesis through targeting gamma-catenin in endothelial cells

    Biochem. Biophys. Res. Commun.

    (2017)
  • Y. Wang et al.

    The emerging function and mechanism of ceRNAs in cancer

    Trends Genet.

    (2016)
  • Y.H. Zhang et al.

    Identifying the RNA signatures of coronary artery disease from combined lncRNA and mRNA expression profiles

    Genomics.

    (2020)
  • N. Ebadi et al.

    Dysregulation of autophagy-related lncRNAs in peripheral blood of coronary artery disease patients

    Eur. J. Pharmacol.

    (2020)
  • Y. Wang et al.

    Dysregulated expression of microRNAs and mRNAs in myocardial infarction

    Am. J. Transl. Res.

    (2015)
  • C.D. Mathers et al.

    Projections of global mortality and burden of disease from 2002 to 2030

    PLoS Med.

    (2006)
  • A.M. Richards et al.

    Can circulating biomarkers identify heart failure patients at low risk?

    Eur. J. Heart Fail.

    (2015)
  • T.M. O’Connell et al.

    Metabolic profiles identify circulating biomarkers associated with heart failure in young single ventricle patients

    Metabolomics.

    (2021)
  • Z. Ward et al.

    Identifying candidate circulating RNA markers for coronary artery disease by deep RNA-sequencing in human plasma

    Cells.

    (2022)
  • X. Zhang et al.

    Genome-wide transcriptome study using deep RNA sequencing for myocardial infarction and coronary artery calcification

    BMC Med. Genet.

    (2021)
  • X. Wang et al.

    lncRNA Mirt1: a critical regulatory factor in chronic intermittent hypoxia exaggerated post-MI cardiac remodeling

    Front. Genet.

    (2022)
  • Y. Zhang et al.

    MicroRNAs or long noncoding RNAs in diagnosis and prognosis of coronary artery disease

    Aging Dis.

    (2019)
  • T. Melak et al.

    Circulating microRNAs as possible biomarkers for coronary artery disease: a narrative review

    EJIFCC.

    (2019)
  • A.E. Pasquinelli

    MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship

    Nat. Rev. Genet.

    (2012)
  • C. Eyileten et al.

    MicroRNAs as diagnostic and prognostic biomarkers in ischemic stroke - a comprehensive review and bioinformatic analysis

    Cells.

    (2018)
  • T. Thum et al.

    Long noncoding RNAs and microRNAs in cardiovascular pathophysiology

    Circ. Res.

    (2015)
  • E.E. Creemers et al.

    Function and therapeutic potential of noncoding RNAs in cardiac fibrosis

    Circ. Res.

    (2016)
  • M. Chen et al.

    Long non-coding RNAs and circular RNAs: insights into microglia and astrocyte mediated neurological diseases

    Front. Mol. Neurosci.

    (2021)
  • N. Malissovas et al.

    Targeting long non-coding RNAs in nervous system cancers: new insights in prognosis, diagnosis and therapy

    Curr. Med. Chem.

    (2019)
  • T.R. Mercer et al.

    Long non-coding RNAs: insights into functions

    Nat. Rev. Genet.

    (2009)
  • N. Schonrock et al.

    Long noncoding RNAs in cardiac development and pathophysiology

    Circ. Res.

    (2012)
  • A. Ebrahimpour et al.

    Novel insights into the interaction between long non-coding RNAs and microRNAs in glioma

    Mol. Cell. Biochem.

    (2021)
  • Q. Hao et al.

    Differential expression profile of long non-coding RNAs in chronic HBV infection: new insights into pathogenesis

    J. Med. Virol.

    (2020)
  • S. Sharma et al.

    Cardiac troponins

    J. Clin. Pathol.

    (2004)
  • M.A. Cortez et al.

    MicroRNAs in body fluids - the mix of hormones and biomarkers

    Nat. Rev. Clin. Oncol.

    (2011)
  • A. Samman Tahhan et al.

    High-sensitivity troponin I levels and coronary artery disease severity, progression, and long-term outcomes

    J. Am. Heart Assoc.

    (2018)
  • R. Navickas et al.

    Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review

    Cardiovasc. Res.

    (2016)
  • Y. D’Alessandra et al.

    Circulating microRNAs are new and sensitive biomarkers of myocardial infarction

    Eur. Heart J.

    (2010)
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