Increased A-to-I RNA editing in atherosclerosis and cardiomyopathies.

Adenosine-to-inosine RNA editing is essential to prevent undesired immune activation. This diverse process alters the genetic content of the RNA and may recode proteins, change splice sites and miRNA targets, and mimic genomic mutations. Recent studies have associated or implicated aberrant editing with pathological conditions, including cancer, autoimmune diseases, and neurological and psychiatric conditions. RNA editing patterns in cardiovascular tissues have not been investigated systematically so far, and little is known about its potential role in cardiac diseases. Some hints suggest robust editing in this system, including the fact that ADARB1 (ADAR2), the main coding-sequence editor, is most highly expressed in these tissues. Here we characterized RNA editing in the heart and arteries and examined a contributory role to the development of atherosclerosis and two structural heart diseases -Ischemic and Dilated Cardiomyopathies. Analyzing hundreds of RNA-seq samples taken from the heart and arteries of cardiac patients and controls, we find that global editing, alongside inflammatory gene expression, is increased in patients with atherosclerosis, cardiomyopathies, and heart failure. We describe a single recoding editing site and suggest it as a target for focused research. This recoding editing site in the IGFBP7 gene is one of the only evolutionary conserved sites between mammals, and we found it exhibits consistently increased levels of editing in these patients. Our findings reveal that RNA editing is abundant in arteries and is elevated in several key cardiovascular conditions. They thus provide a roadmap for basic and translational research of RNA as a mediator of atherosclerosis and non-genetic cardiomyopathies.

RNA editing of Filamin A pre-mRNA regulates vascular contraction and diastolic blood pressure.

Epitranscriptomic events such as adenosine-to-inosine (A-to-I) RNA editing by ADAR can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin crosslinking protein Filamin A (FLNA) mediates a Q-to-R transition in the interactive C-terminal region. While FLNA editing is conserved among vertebrates, its physiological function remains unclear. Here, we show that cardiovascular tissues in humans and mice show massive editing and that FLNA RNA is the most prominent substrate. Patient-derived RNA-Seq data demonstrate a significant drop in FLNA editing associated with cardiovascular diseases. Using mice with only impaired FLNA editing, we observed increased vascular contraction and diastolic hypertension accompanied by increased myosin light chain phosphorylation, arterial remodeling, and left ventricular wall thickening, which eventually causes cardiac remodeling and reduced systolic output. These results demonstrate a causal relationship between RNA editing and the development of cardiovascular disease indicating that a single epitranscriptomic RNA modification can maintain cardiovascular health.

Landscape of adenosine-to-inosine RNA recoding across human tissues.

RNA editing by adenosine deaminases changes the information encoded in the mRNA from its genomic blueprint. Editing of protein-coding sequences can introduce novel, functionally distinct, protein isoforms and diversify the proteome. The functional importance of a few recoding sites has been appreciated for decades. However, systematic methods to uncover these sites perform poorly, and the full repertoire of recoding in human and other mammals is unknown. Here we present a new detection approach, and analyze 9125 GTEx RNA-seq samples, to produce a highly-accurate atlas of 1517 editing sites within the coding region and their editing levels across human tissues. Single-cell RNA-seq data shows protein recoding contributes to the variability across cell subpopulations. Most highly edited sites are evolutionary conserved in non-primate mammals, attesting for adaptation. This comprehensive set can facilitate understanding of the role of recoding in human physiology and diseases.

Natural History of Moderate Aortic Stenosis with Preserved and Low Ejection Fraction.

BACKGROUND: There is a shortage of data concerning the natural history of patients with moderate aortic stenosis (AS). The aim of this study was to assess the effect of moderate AS on mortality in the general population and in the subgroups of patients with moderate AS and reduced ejection fractions (EF) and patients with moderate AS and low aortic valve gradients. The study was not designed to address the applicability of treatment in this population. METHODS: Outcomes were compared between patients with moderate AS and a propensity-matched cohort (1:3 ratio) without AS. The primary outcome was survival until end of follow-up. RESULTS: Among approximately 40,000 patients who underwent echocardiographic evaluations between 2011 and 2016, 952 had moderate AS. Median follow-up duration was 181 weeks (interquartile range, 179-182 weeks) for the entire cohort and 174 weeks (interquartile range, 169-179 weeks) for the propensity-matched groups. Propensity matching successfully balanced most preexisting clinical differences. Increased mortality was observed in the group of patients with moderate AS before propensity matching and persisted following propensity matching (median survival 4.1 vs 5.2 years, P = .008). Survival rates and corresponding standard errors at 1, 2, 3, and 5 years were 80 ± 1% versus 82 ± 0.7%, 70 ± 1.5% versus 74 ± 0.8%, 62 ± 1.7% versus 66 ± 0.9%, and 47 ± 2.4% versus 52 ± 1.3%, respectively. A survival difference was similarly observed for the subgroup analyses of moderate AS and reduced ejection fraction (P = .028) and moderate AS and low aortic valve gradients (P = .039). CONCLUSIONS: Moderate AS is associated with increased mortality. The increased mortality was also observed in the subgroups of patients with either reduced ejection fraction or low aortic valve gradients.