Long Noncoding RNA Discovery in Cardiovascular Disease

Despite substantial progress in understanding disease mechanisms and the approval of multiple new therapies, for the first time in 3 decades, we are witnessing an increase in overall cardiovascular deaths. Recently, the discovery of an attractive group of molecules known as long noncoding RNAs (lncRNAs) has introduced a new catalog of diagnostic and therapeutic opportunities for cardiovascular risk mitigation. For half a century, the principle that proteins are the primary protagonists of cellar functions has dominated the molecular biology landscape. It has long been appreciated that classes of RNAs, such as transfer RNAs and ribosomal RNAs, have infrastructural importance without encoding for proteins. Thomas Cech and Sidney Altman shared the noble prize in chemistry for their discovery of biological properties of ribozymes, specialized RNAs that catalyze biochemical reactions. However, the notion that RNAs that biochemically resemble mRNA, yet do not template protein, serve important functions had gone largely untested for many years. A major turning point in our understanding of the complex role of RNAs in genome regulation came with the sequencing of the human genome. Surprisingly, protein-coding genes account for only 2% of the human genome, despite the fact that >90% of the genome is actively transcribed. This apparent discrepancy contradicted the presumed efficiency by which mammalian cells were believed to operate. After all, why would living organisms waste so much of the cellular machinery and resources on a process of little biological consequence? A barrage of subsequent studies revealed that this pervasive transcriptional pattern is in fact biologically relevant, thus catalyzing interest in lncRNAs as players in both physiology and disease. Today lncRNAs are considered important contributors to the diverse RNA community existing within living cells (Figure 1A). However, the substantial overlap between subtypes of lncRNAs presents a challenge to a uniform and consistent classification scheme. The vast majority of definitions describing lncRNAs and related transcripts is shown in Figure 1B. To date, most studies on lncRNAs have focused on their roles in development and differentiation, and many of these findings have had implications for cancer biology. More recently, evidence has begun to emerge that lncRNAs may also participate in diverse additional biological processes and that abnormalities of lncRNAs may be linked to human disease. Cardiovascular biology and disease is one such emerging area of interest. For example, the lncRNA ANRIL was identified in multiple human genome-wide association studies as the most robust predictor of atherosclerotic risk and cardiovascular events. The precise molecular mechanisms of ANRIL, as is the case with vast majority of lncRNAs, remain poorly understood. The past few years have witnessed a rapid increase in number of studies addressing the roles of lncRNAs in cardiovascular disease. lncRNAs have now been associated with diverse cardiovascular conditions and associated risk factors, including pathological hypertrophy and development, vascular disease, atherosclerosis, dyslipidemia, and metabolic Review