Introduction
Theranostics refers to the combined use of diagnostics and therapeutics. RNAs, which have recently demonstrated increasing capacity to be used as diagnostic tools - owing to their presence in biofluids - and therapeutic targets - owing to their regulation of disease processes - constitute a reservoir of novel theranostic targets, in the cardiovascular field and beyond (1).
The expanding RNA landscape: from miRNAs to lncRNAs and circRNAs
The RNA family is vast, with protein-coding RNAs (messenger RNAs) and non-protein coding RNAs (ncRNAs). Among the latter, the short microRNAs have received much attention in past 15 years and may serve to personalize healthcare (2). Long ncRNAs (lncRNAs), which can be of linear (lncRNAs) or circular (circRNAs) form, also possess biomarker and therapeutic potential for cardiovascular disease (3). Initial work showed associations between heart failure development after myocardial infarction (MI) and circulating levels of linear lncRNAs (4,5).
circHIPK2: a novel regulator of post-MI inflammation and cardiac dysfunction
The recent paper by Jung and colleagues (6) reports findings from a study focusing on a novel circRNA, circHIPK2. Upregulated in inflammatory cardiac macrophages after MI, circHIPK2 was found to act as a molecular switch for macrophage polarization. Gain- and loss-of-function experimental approaches in vitro and in vivo showed that circHIPK2 was a trigger of a pro-inflammatory phenotype in macrophages, leading to cytokine production, fibrosis and reduced cardiac function. Silencing circHIPK2 had beneficial effects, reducing the pro-inflammatory phenotype of macrophages and improving cardiac function. Using living myocardial slices from patients with heart failure, authors confirmed the therapeutic potential of circHIPK2 inhibition. In another study, the circRNA Cdr1as was down-regulated in macrophages and cardiomyocytes in the heart of mice subjected to MI, and over-expressing Cdr1as showed anti-inflammatory effects accompanied with improved left ventricular function (7). Therefore, targeting immune cells by circRNA-based therapies appear a promising approach to treat MI and reduce the development of subsequent heart failure.
Circular RNAs as biomarkers and therapeutic targets after myocardial infarction
Previous investigations reported the potential of circRNAs as biomarkers predicting heart failure after MI. The circRNA MICRA (Myocardial Infarction-associated Circular RnA) was found to be a promising prognostic biomarker of left ventricular remodelling after MI (8). Other circRNAs, summarized in 3, have shown potential as “actionable” biomarker of ischemic heart disease. The study by Jung and colleagues (6) adds another candidate, circHIPK2 to the list of circRNAs with therapeutic potential. Whether circHIPK2 could also be used as a circulating prognostic biomarker after MI remains to be determined.
Outlook: advancing RNA theranostics towards clinical cardiovascular care
Overall, RNA theranostics holds potential to advance cardiovascular healthcare and improve patient outcomes and quality of life, as covered in details in the Themed Issue “Noncoding RNA therapeutics” (9). NcRNAs may be associated with imaging technologies to improve prognostication (10). Continuous support from funding and research agencies are needed to translate ncRNAs to disease prevention and management (1)1.
