LncRNAs in vascular biology and disease

Abstract

Accumulating studies indicate that long non-coding RNAs (lncRNAs) play important roles in the regulation of diverse biological processes involved in homeostatic control of the vessel wall in health and disease. However, our knowledge of the mechanisms by which lncRNAs control gene expression and cell signaling pathways is still nascent. Furthermore, only a handful of lncRNAs has been functionally evaluated in response to pathophysiological stimuli or in vascular disease states. For example, lncRNAs may regulate endothelial dysfunction by modulating endothelial cell proliferation (e.g. MALAT1, H19) or angiogenesis (e.g. MEG3, MANTIS). LncRNAs have also been implicated in modulating vascular smooth muscle cell (VSMC) phenotypes or vascular remodeling (e.g. ANRIL, SMILR, SENCR, MYOSLID). Finally, emerging studies have implicated lncRNAs in leukocytes activation (e.g. lincRNA-Cox2, linc00305, THRIL), macrophage polarization (e.g. GAS5), and cholesterol metabolism (e.g. LeXis). This review summarizes recent findings on the expression, mechanism, and function of lncRNAs implicated in a range of vascular disease states from mice to human subjects. An improved understanding of lncRNAs in vascular disease may provide new pathophysiological insights and opportunities for the generation of a new class of RNA-based biomarkers and therapeutic targets.

Keywords: cardiovascular disease; lncRNAs; non-coding RNAs; vascular biology.

Figure 1. Cellular functions of long non-coding RNAs (lncRNAs)

LncRNAs regulate gene expression by multiple mechanisms. Nuclear-localized lncRNA can guide transcription factors (TF) or protein complexes to specific sites in the genome (A) or sequester the TF and repress their function (B). They can induce histone modifications and guide chromatin remodeling complexes to the correct chromosomal locations (C) or induce chromosomal looping to increase association between enhancer and promoter regions (D). LncRNAs can regulate nucleocytoplasmic shuttling (E) of nuclear factor of activated T cells (NFAT) or alternative splicing of pre-mRNAs (F). In the cytoplasm, lncRNAs can regulate mRNA stability (G) and control translational events (H), sponge miRNAs (J) and act as a scaffold for proteins complexes (I). Further regulatory functions may include stabilization of ribonucleoprotein (RNP) complexes (K) or protein phosphorylation and activation of signaling pathways (L); Circular lncRNAs are formed by RNA splicing and were observed to act as miRNA sponges, or regulate the maturation of ribosomal RNAs (M). Finally, some lncRNAs are released in exosomes or microvesicles, potentially facilitating cell-to-cell communication (N).

Figure 2. LncRNAs implicated in vascular disease

Highlighted lncRNAs involved in endothelial cell biology, vascular smooth muscle cell proliferation, leukocyte inflammation, and lipid metabolism.