lncRNA/MicroRNA interactions in the vasculature

Abstract

MicroRNA (miRNA) have gained widespread attention for their role in diverse vascular processes including angiogenesis, apoptosis, proliferation, and migration. Despite great understanding of miRNA expression and function, knowledge of long noncoding RNA (lncRNA) molecular mechanisms still remains limited. The influence of miRNA on lncRNA function, and the converse, is now beginning to emerge. lncRNA may regulate miRNA function by acting as endogenous sponges to regulate gene expression and miRNA have been shown to bind and regulate lncRNA stability. A detailed understanding of the molecular and cellular effects of lncRNA-miRNA-mediated interactions in vascular pathophysiology could pave the way for new diagnostic markers and therapeutic approaches, but first there is a requirement for a more detailed understanding of the impact of such regulatory networks.

Figure 1

Vascular injury initiating factors. Vascular injury is a multicomponent condition resulting from a plethora of initiating factors, such as sheer stress, endothelial denudation caused by stent deployment, and smoke toxins. This leads to alterations in endothelial function such as a reduction in antithrombotic agents such as nitric oxide (NO) and prostaglandins, initiation of inflammatory signaling cascades, upregulation of adhesion molecules, an increase in reactive oxygen species (ROS), and decreased barrier function. Downward arrows indicate the initiating factors causing endothelial injury while the upward arrows indicate the vascular disease or complication resulting from the initiating factor. Ultimately, changes in endothelial function and release of inflammatory stimuli and growth factors from inflammatory cells impairs the function of the underlying vascular smooth muscle cells causing increased proliferation and migration in response to injury.

Figure 2

Basic miRNA processing pathway. MiRNA are transcribed from DNA and are cleaved into pre‐miRs via the actions of DROSHA. Pre‐miRs are then exported into the cytoplasm via exportin‐5 and processed into mature miRNA via the actions of DICER. Following their processing the mature miRNA will then associate with a complex called RNA induced silencing complex (RISC) to induce either translational repression or mRNA degradation. Adapted from Ref. 67.

Figure 3

Schematic diagram of four archetypes of lncRNA mechanisms. lncRNA can exert their function through complementary binding to RNA, DNA, and protein molecules. Adapted from Ref. 26. (a) lncRNA may act as signals of transcriptional activity and may indicate gene regulation. (b) lncRNA may act as endogenous sponges for molecules such as miRNA, thus reducing the bioavailability of the molecule, altering cellular function. (c) lncRNAs can act as guides and tethers for chromatin‐modifying complexes, thus aiding in the recruitment to DNA and contributing to tissue‐specific gene expression. (d) lncRNA may act as scaffolds bridging essential proteins required for gene or cellular regulation.

Figure 4

lncRNA: miRNA‐mediated interactions. Schematic diagram highlighting the routes via which lncRNA and miRNA may interact. (a) lncRNA‐miRNA sponge: binds and sequesters miRNA away from their site of action, thus reducing their function within the cell. (b) lncRNA generating miRNA. lncRNA may host miRNA both within their exons and introns. (c) Some lncRNA are degraded by miRNA.

Figure 5

Overview of lncRNA‐mediated interactions in vascular smooth muscle and endothelial cells during vascular disease. Many novel lncRNA have been identified to bind and regulated miRNA function. Outside labels indicate the lncRNA involved in the interaction. Inner ring highlights the miRNA associated with the interacting lncRNA.