The emerging landscape of non-conventional RNA functions in atherosclerosis

Most of the human genome is transcribed into non-coding RNAs (ncRNAs), which encompass a heterogeneous family of transcripts including microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and others. Although the detailed modes of action of some classes are not fully elucidated, the common notion is that ncRNAs contribute to sculpting gene expression of eukaryotic cells at multiple levels. These range from the regulation of chromatin remodeling and transcriptional activity to post-transcriptional regulation of messenger RNA splicing, stability, and decay. Many of these functions ultimately govern the expression of coding and non-coding genes to affect diverse physiological and pathological mechanisms in vascular biology and beyond. As such, different classes of ncRNAs emerged as crucial regulators of vascular integrity as well as active players in the pathophysiology of atherosclerosis from the early stages of endothelial dysfunction to the clinically relevant complications. However, research in recent years revealed unexpected findings such as small ncRNAs being able to biophysically regulate protein function, the glycosylation of ncRNAs to be exposed on the cell surface, the release of ncRNAs in the extracellular space to act as ligands of receptors, and even the ability of non-coding portion of messenger RNAs to mediate structural functions. This evidence expanded the functional repertoire of ncRNAs far beyond gene regulation and highlighted an additional layer of biological control of cell function. In this Review, we will discuss these emerging aspects of ncRNA biology, highlight the implications for the mechanisms of vascular biology and atherosclerosis, and discuss possible translational implications.