MicroRNAs in cardiovascular disease: an introduction for clinicians

Abstract

MicroRNAs (miRNAs) are small, non-coding, RNA molecules approximately 22 nucleotides in length which act as post-transcriptional regulators of gene expression. Individual miRNAs have been shown to regulate the expression of multiple genes. Conversely, the expression of individual genes can be regulated by multiple miRNAs. Consequently, since their discovery just over 20 years ago, miRNAs have been identified as key regulators of complex biological processes linked to multiple cardiovascular pathologies, including left ventricular hypertrophy, ischaemic heart disease, heart failure, hypertension and arrhythmias. Furthermore, since the finding that miRNAs are present in the circulation, they have been investigated as novel biomarkers, especially in the context of acute myocardial infarction (AMI) and heart failure. While there is little convincing evidence that miRNAs can outperform traditional biomarkers, such as cardiac troponins, in the diagnosis of AMI, there is potential for miRNAs to complement existing risk prediction models and act as valuable markers of post-AMI prognosis. Encouragingly, the concept of miRNA-based therapeutics is developing, with synthetic antagonists of miRNAs (antagomiRs) currently in phase II trials for the treatment of chronic hepatitis C virus infection. In the cardiovascular field, promising preclinical studies suggest that they could be useful in treating disorders ranging from heart failure to dyslipidaemia, although several challenges related to specificity and targeted delivery remain to be overcome. Through this review, we provide clinicians with a brief overview of the ever-expanding world of miRNAs.

Figure 1

Biogenesis of microRNA. MicroRNA genes are transcribed by RNA polymerase II into molecules approximately 2 kb long called primary miRNAs (pri-miRNAs). Within the nucleus, these are cleaved into precursor miRNAs (pre-miRNAs) by Drosha, an RNase III enzyme, in association with DGCR8, an RNA-binding protein. Pre-miRNAs are approximately 60–100 nucleotides in length and have a hairpin structure. Interestingly, the presence of pre-miRNAs that are processed by direct splicing of introns (and thereby bypassing Drosha processing; dashed arrow) has also been reported; these are known as mirtrons.^w4 Both pre-miRNAs and mirtrons are actively transported to the cytoplasm by the Ran-GTP dependent transporter, Exportin 5. Within the cytoplasm, pre-miRNAs are further cleaved by Dicer (another RNase III enzyme) generating unstable double-stranded miRNA duplexes—these duplexes are approximately 22 nucleotides in length and contain a functional miRNA ‘guide’ strand and a ‘passenger’ stand (previously termed miR-X*). Subsequently, the duplex is unwound and the passenger strand degraded, leaving the guide strand to enter the RNA-induced silencing complex (RISC) by associating with Argonaute proteins. Image adapted from Wienholds and Plasterk with permission from Elsevier.

Figure 2

Schematic representation of microRNA mechanism of action. In the first step of protein synthesis, the DNA which codes for the protein of interest is converted into mRNA (transcription). (A) In the absence of miRNA, the mRNA transcripts are converted into protein (translation). (B) In the presence of miRNA with partial, near-perfect complementarity to the mRNA of interest, miRNA binds in the 3′ UTR and represses translation—inhibiting protein synthesis. (C) In the presence of miRNA with perfect complementarity, miRNA binding in the 3′ UTR is thought to inhibit protein synthesis through the induction of mRNA degradation. In humans, perfect complementarity is rare, with varying degrees of partial complementarity the predominant situation.

Figure 3

Circulating microRNAs associated with acute coronary syndromes and coronary artery disease. MicroRNAs with a double border have been linked to the associated trait by more than one study—for details online supplementary tables S2 and S4.

Figure 4

Circulating microRNAs associated with a diagnosis of heart failure. MicroRNAs with a double border have been linked to heart failure by more than one study—for details online supplementary table S5.