Extracellular/circulating microRNAs and their potential role in cardiovascular disease

Abstract

microRNAs (miRs, miRNAs) are small non-coding RNAs that regulate hundreds of gene expression. Numerous studies have demonstrated that miRNAs are not only found intracellularly, but also detectable outside cells, including various body fluids (i.e. serum, plasma, saliva, urine, breast milk, and tears). Interestingly, ~90% of extracellular miRNAs are packaged with proteins (i.e. Ago2, HDL, and other RNA-binding proteins) and ~10% are wrapped in small membranous particles (i.e. exosomes, microvesicles, and apoptotic bodies). It is believed that these extracellular miRNAs mediate cell-to-cell communication. Recent studies further indicated that the level and composition of these extracellular/circulating miRNAs correlated well with disease or injurious conditions. Uncovering the potential role of extracellular miRNAs in the heart is just emerging. This review will highlight recent exciting findings in the regulation of miRNA biogenesis and secretion, their functional roles in paracrine signaling, and the potential as non-invasive biomarkers for cardiovascular disease.

Figure 1

Schematic representation of microRNA (miRNA) biogenesis. miRNA is mainly transcribed by RNA polymerase II, followed by the Drosha complex cleaves off to generate the pre-miRNA that is exported to the cytoplasm by Exportin-5. Subsequent to Dicer cleavage, the miRNA duplex is unwound and the passenger strand degraded. The guide strand (mature miRNA) is then incorporated into the miRISC where gene silence can be accomplished via mRNA target cleavage, translational repression, or mRNA deadenylation.

Figure 2

Cellular releases (A) and uptake (B) of miRNAs. (A) Extracellular miRNAs may be contained within vesicles, including microvesicles, exosomes, and apoptotic bodies, as well as within proteins such as Ago2, HDL, and other RNA-binding proteins. (B) Extracellular miRNAs may potentially interact with recipient cells via direct fusion, internalization, receptor-mediated interactions and other possible mechanisms.