Circulating microRNA as a Biomarker for Coronary Artery Disease

Abstract

Coronary artery disease (CAD) is the leading cause of sudden cardiac death in adults, and new methods of predicting disease and risk-stratifying patients will help guide intervention in order to reduce this burden. Current CAD detection involves multiple modalities, but the consideration of other biomarkers will help improve reliability. The aim of this narrative review is to help researchers and clinicians appreciate the growing relevance of miRNA in CAD and its potential as a biomarker, and also to suggest useful miRNA that may be targets for future study. We sourced information from several databases, namely PubMed, Scopus, and Google Scholar, when collating evidentiary information. MicroRNAs (miRNA) are short, noncoding RNAs that are relevant in cardiovascular physiology and pathophysiology, playing roles in cardiac hypertrophy, maintenance of vascular tone, and responses to vascular injury. CAD is associated with changes in miRNA expression profiles, and so are its risk factors, such as abnormal lipid metabolism and inflammation. Thus, they may potentially be biomarkers of CAD. Nevertheless, there are limitations in using miRNA. These include cost and the presence of several confounding factors that may affect miRNA profiles. Furthermore, there is difficulty in the normalisation of miRNA values between published studies, due to pre-analytical variations in samples.

Keywords: biomarkers; coronary artery disease; microRNA; noncoding RNA.

Figure 1

MiRNA biogenesis and their means of transcriptional silencing. RNA Pol II: RNA polymerase II; miRNA: microRNA; RanGTP: Ran coupled to guanosine triphosphate; RISC: RNA-induced silencing complex; Poly(A) tail: poly-adenosine tail; 80S ribosome: eukaryotic ribosome. (A) Within the nucleus (blue area), miRNA are initially transcribed (e.g., from an miRNA gene) from DNA by RNA polymerase II (yellow) in the form of primary miRNA, or pri-miRNA, which contain stem-loop structures. The enzyme Drosha (purple) proceeds to cleave these stem–loop structures from the rest of the transcript, and these structures are now defined as precursor miRNA, or pre-miRNA. These are then exported from the nucleus via exportin 5 coupled to the Ran cycle. (B) Once in the cytosol (yellow area), the enzyme Dicer recognises pre-miRNA and cleaves them to produce mature miRNA molecules with two nucleotide overhangs on their 3′ ends. This molecule is then incorporated into an RNA-induced silencing complex (RISC, green) and the passenger strand (red backbone) is destroyed. This results in an active RISC complex. (C) The active RISC complex uses the guide strand of the miRNA (blue backbone) to target mRNA transcripts, specifically those that are complementary to the seed sequence of the guide strand. Through translational repression and RNA decay, miRNA reduce the expression of certain genes through RISC. Also note that the poly(A) tail is shown in pink. Ago2: Argonaute 2; DGCR8: DiGeorge syndrome critical region 8.

Figure 2

Export pathways for miRNA and means of interaction with other cells/cell of origin as a potential means of signalling. (A) The autocrine pathway, whereby extracellular miRNAs re-enter the cell from which they originated. (B) The paracrine pathway, whereby extracellular miRNAs are transported towards and enter cells of the same or different type to the miRNA’s cell of origin. (C) The endocrine pathway, whereby extracellular miRNAs enter the circulation and are thus transported to cells in other tissues/organs. Ago2: Argonaute 2; miRNA: microRNA.

Figure 3

Associations between miRNA in different cells and constituent pathways in coronary artery disease (CAD) pathogenesis. Pathological alterations in the phenotypes of particular cells of the circulatory system, in addition to normal homeostatic processes, are core to the development of CAD (shown in blue, phenotypes in red, pathophysiological processes in purple). Various miRNAs have been identified as being associated with these pathological developments (shown in green), with previous studies showing that they may be implicated in particular contributing mechanisms. VSMC: vascular smooth muscle cell.