The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease

Abstract

The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins. Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states. Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease. Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus.

Keywords: RNAs; cardiovascular development; cardiovascular disease; cardiovascular system; long non-coding RNAs; non-coding RNAs; therapy; transcriptomics; vascular disease.

Figure 1

Classification of lncRNAs by Mechanism of Action Signal lncRNAs respond to specific stimuli and thus show expression specific to cell type. Decoys bind transcription factors and other proteins away from their target site, repressing transcription. Guides interact with regulatory proteins, forming ribonucleoprotein complexes, and direct them to their target sites in subcellular locations. Scaffolds serve as platforms to bring different proteins together, both in the cytoplasm and in the nucleus, activating or repressing transcription. Enhancers are regulatory sequences in which transcription factors bind to initiate transcription; these regions of the genome produce several transcripts, enhancer lncRNAs, which act in cis to regulate expression of target genes. In the cytoplasm, lncRNAs can activate or inhibit translation by binding to target mRNAs. They can also regulate protein trafficking and signaling, such as phosphorylation. Sponging miRNAs is another way lncRNAs (including circular RNAs) regulate gene expression post-transcriptionally.

Figure 2

lncRNAs that Are Up- or Downregulated in Cardiovascular Diseases The human, mouse, or rat symbol indicates in which organism the lncRNA has been described. *MIAT is downregulated in ST-elevation myocardial infarction (STEMI) patients compared to non-ST-elevation myocardial infarction (NSTEMI) patients; it correlates with hypertension, but there is no change in regulation.

Figure 3

Biological Context of lncRNAs Associated with Cardiovascular Disease and Their Mechanism of Action CAD, coronary artery disease; MI, myocardial infarction.

Figure 4

H19 Is Associated with Hypertension, CAD, Atherosclerosis, Ischemia, and Heart Failure Although mechanistic insights into the role of H19 in cardiovascular disease are lacking, methylation regulation and sponging of miRNAs have been suggested and may overlap among diseases. Polymorphisms have been correlated with blood pressure and CAD. H19 action as a sponge for the miRNA let-7 family has been linked to CAD and could be a possible mechanism in hypoxia. In heart failure, it acts by interacting with protein to regulate cardiac fibrosis and is a precursor of miR-675, which targets an inducer of hypertrophy.