Transcription of a large part of the human genome results in RNA transcripts that have limited or no protein-coding potential. These include long noncoding RNAs (lncRNAs), which are defined as being ≥200 nucleotides long. Unlike microRNAs, which have been extensively studied, little is known about the functional role of lncRNAs. However, studies over the past 5 years have shown that lncRNAs interfere with tissue homeostasis and have a role in pathological processes, including in the kidney and heart. The developmental expression of the microRNA sponge H19, for example, is altered in the kidneys of embryos carried by hyperglycaemic mothers, and the lncRNA Malat1 regulates hyperglycaemia-induced inflammation in endothelial cells. Putative roles for other lncRNAs have been identified in conditions such as heart failure, cardiac autophagy, hypertension, acute kidney injury, glomerular diseases, acute allograft rejection and renal cell carcinoma.
LncRNAs in cardiac development and disease
LncRNAs regulate cardiac development and disease through various mechanisms. Cardiac development: Bvht regulates cardiac lineage commitment and cardiac gene expression by altering the expression of MESP1 and the activity of SUZ12. Loss of TERMINATOR, ALIEN or PUNISHER results in impaired cardiovascular development. Heart failure: Chrf functions as a sponge for miR-489, which protects against heart failure development by targeting MYD88. Mdrl downregulates miR-361, which in turn inhibits pri-miR-484 processing so reduces mitochondrial fission and apoptosis. Circulating levels of MT-LIPCAR predict adverse cardiac remodelling after myocardial infarction. In response to cardiac stress the BRG1–HDAC–PARP chromatin repressor complex is activated, which inhibts Mhrt transcription, culminating in cardiac failure. The micropeptide MLN directly interacts with SERCA, thereby inhibiting Ca2+ uptake into the sarcoplasmic reticulum, leading to poor exercise performance. Endothelial function: hypoxic stress induces an increase in the level of MALAT1, which promotes the proliferation and migration of endothelial cells and a reduction in apoptosis. Endothelial hypoxia also results in increases in the levels of LINC00323 and MIR503HG, which promotes angiogenesis by regulating the levels of GATA2 and sirtuin1. Myocardial infarction: increased expression of Mirt1 and Mirt2 preserves ejection fraction during myocardial infarction by influencing a set of genes that are associated with left ventricular remodelling. Autophagy: APF inhibits miR-188-3p, which leads to increased ATG7 levels, resulting in an increase of autophagy and myocardial infarction.