CircNCX1: the "Lord of the Ring" in the Heart - Insight into Its Sequence Characteristic, Expression, Molecular Mechanisms, and Clinical Application.

Circular RNAs (circRNAs) are covalently closed single-stranded RNAs with regulatory activity and regarded as new types of therapeutic targets in diseases such as cancers. By means of RNA-Seq technology, numerous cardiac circRNAs were discovered. Although some candidates were detected to involve in heart disease in murine model, relative low sequence conservation and expression level of their human homologs might result in an insignificant, even distinct effect in the human heart. Therefore, the therapeutic significance of circRNAs should be more strictly considered. It is also necessary to discuss which circRNA is suitable for being applied in heart disease treatment. Here, we are willing to introduce a ~ 1830 nt circular transcript generated from single exon of sodium/calcium exchanger 1 (ncx1) gene (also called solute carrier family 8 member A1, slc8a1), usually named circNCX1 or circSLC8A1, which is gradually coming into our view. circNCX1 is one of the most cardiac-enriched circRNAs. It is widely existent in vertebrate and relatively conserved, indicating its indispensability during the evolution of species. Indeed, circNCX1 was shown to involve in heart development by some expression analysis. It was further revealed that the dysregulation of circNCX1 is one of the key pathogeneses of heart diseases including ischemic cardiac injury and hypertrophic cardiomyopathy. To make the significance of circNCX1 in the heart clear, we comprehensively dissected circNCX1 in the aspects of its parental gene structure, conservation, biogenesis and expression profiles, function, molecular mechanisms, and clinical application in this review. New medicine or therapeutic schedules based on circNCX1 are expected in the future.