The biological function and potential mechanism of long non-coding RNAs in cardiovascular disease

Abstract

Long non-coding RNAs (lncRNAs), as part of the family of non-protein-coding transcripts, are implicated in the occurrence and progression of several cardiovascular diseases (CVDs). With recent advances in lncRNA research, these molecules are purported to regulate gene expression at multiple levels, thereby producing beneficial or detrimental biological effects during CVD pathogenesis. At the transcriptional level, lncRNAs affect gene expression by interacting with DNA and proteins, for example, components of chromatin-modifying complexes, or transcription factors affecting chromatin status. These potential mechanisms suggest that lncRNAs guide proteins to specific gene loci (eg promoter regions), or forestall proteins to specific genomic sites via DNA binding. Additionally, some lncRNAs are required for correct chromatin conformation, which occurs via chromatin looping in enhancer-like models. At the post-transcriptional level, lncRNAs interact with RNA molecules, mainly microRNAs (miRNAs) and mRNAs, potentially regulating CVD pathophysiological processes. Moreover, lncRNAs appear to post-transcriptionally modulate gene expression by participating in mRNA splicing, stability, degradation and translation. Thus, the purpose of this review is to provide a comprehensive summary of lncRNAs implicated in CVD biological processes, with an emphasis on potential mechanisms of action.

Keywords: cardiovascular diseases; long non-coding RNA; microRNA; post-transcriptional regulation; transcriptional regulation.

FIGURE 1

Transcriptional regulation of cardiovascular lncRNAs via interactions with multiple chromatin‐modifying complexes. The mode of action of cardiac lncRNAs, such as Fendrr, is shown in the guiding scaffold model (A, C); In the trapped scaffold model, Bvht and Chaer detach histone‐modifying enzymes, such as PRC2, from target genome sites (B). lncRNA, long non‐coding RNA; PRC, polycomb repressive complex; TrxG/MLL, trithorax/mixed lineage leukaemia

FIGURE 2

Models of enhancer activity of lncRNAs. In the chromatin looping model, lncRNA‐LEENE (red line) is transcribed from enhancer non‐coding genes. LEENE RNA transcripts recruit RNAP II to the eNOS promoter and bridge the enhancer of the non‐coding LEENE gene and the promoter of the eNOS gene. As a result, eNOS transcription levels are enhanced. lncRNA, long non‐coding RNA; eNOS, endothelial nitric oxide synthase; RNAP II, RNA polymerase II

FIGURE 3

Cardiac lncRNAs, which act as miRNAs sponges, are involved in the regulation of cardiomyocyte apoptosis, necrosis, autophagy, hypertrophy and cardiac fibrosis. A solid arrow indicates promotion; a dashed arrow represents inhibition; Cardioprotective lncRNAs are in bold type; Heart‐damaging lncRNAs are in italics