Emerging research suggests reversible RNA editing mechanisms may influence heart disease biology while opening new avenues for biomarkers and next-generation cardiovascular therapies.
Review: RNA editing in cardiovascular health and disease. Image Credit: sizsus art / Shutterstock
In a recent mini-review published in the journal Communications Biology, researchers summarize emerging but still evolving evidence exploring potential links between dysregulated post-transcriptional RNA modifications and cardiovascular disease (CVD) risk. Post-transcriptional RNA modification, specifically adenosine-to-inosine (A-to-I) editing, is a key regulatory mechanism that alters RNA structure and function without changing the underlying DNA sequence.
Review findings suggest that RNA editing is not merely a byproduct of cellular activity but appears essential for normal development and cardiovascular homeostasis, noting emerging associations rather than definitive causal relationships between editing and several CVDs, including coronary artery disease (CAD), atherosclerosis, hypertension, and heart failure (HF). Future research aimed at understanding these associations and the mechanisms that govern them may help inform future therapeutic strategies, although clinical applications remain investigational.
Biological Basis of A-to-I RNA Editing in the Cardiovascular System
The traditional "Central Dogma" of molecular biology, for decades, posited that information flows strictly from DNA to RNA to protein. However, the discovery of RNA editing in 1986, and in mammals by 1989, introduced an additional regulatory layer of molecular complexity in which the RNA "intermediate" is modified after transcription.
Subsequent research revealed that the most prevalent form of RNA editing is A-to-I editing, in which ADAR enzymes convert adenosine nucleotides to inosine. Crucially, studies have observed that since the body's translation machinery reads inosine as guanosine, a single edit can in some cases alter RNA stability, splicing, or protein function.
Research aimed at identifying the physiological (cardiovascular-specific) function of post-transcriptional RNA modifications has revealed that, in the heart and blood vessels, this process may contribute to maintaining cellular balance and immune tolerance rather than acting solely as a protective mechanism. For example, RNA editing has been reported to help prevent inappropriate activation of the innate immune system against the body’s own double-stranded RNA.
However, effects appear context-dependent. Deficiencies in editing have been associated with, but not universally shown to cause, autoimmune disorders, cancers, and neurological conditions. Accordingly, current research is examining, with caution, how this "molecular proofreading" specifically governs the modulation of cardiovascular growth, maintenance, and responses to injury.
Methodological Approaches and Editome Mapping
The present mini-review aims to elucidate the current literature on RNA editing-CVD associations, leveraging data generated by high-throughput technologies such as RNA sequencing (RNA-seq) to systematically analyze millions of potential editing sites, particularly within "Alu elements", repetitive DNA sequences where most human RNA editing occurs.
Associated metrics, including the Alu editing index (AEI), which quantifies the total level of A-to-I editing within a tissue sample, are increasingly used as approximate global indicators rather than definitive functional measures for mapping the "editome" of the human heart.
Notably, conventional research relies heavily on animal models to establish cause-and-effect ("causation"). For instance, "knockout" mice, murine models in which specific genes such as Adar1 or Adar2 are deleted, are frequently used to examine the developmental consequences of RNA editing.
To further validate observations within a molecular framework, studies leverage RT-qPCR and Sanger sequencing to confirm single-nucleotide changes in specific transcripts. Additionally, while informative, such approaches still require integration with functional studies. Publicly accessible scientific databases, such as REDIportal, now host approximately 16 million putative A-to-I editing sites, providing a substantial dataset for researchers to identify and model disease-related patterns.
Associations Between RNA Editing and Specific Cardiovascular Diseases
The present review underscores that RNA editing is closely linked to development and survival in experimental models, rather than being universally indispensable across contexts. Mice completely lacking the Adar1 gene ubiquitously die by embryonic day 10.5 due to widespread cell death in the heart and other tissues.
When Adar1 is deleted only in cardiomyocytes (heart muscle cells), embryos exhibit severe developmental abnormalities, potentially due to reduced cell proliferation and increased apoptosis (programmed cell death).
The study highlights several key discoveries regarding specific CVDs, including:
- Coronary artery disease (CAD): Variants that increase the risk of CAD have been associated with altered, often reduced but not uniformly so, A-to-I editing in some cardiovascular tissues.
- Atherosclerosis: In vascular smooth muscle cells (VSMCs), the loss of ADAR1 was observed to increase the size and calcification of atherosclerotic lesions. Conversely, editing of the CTSS gene (cathepsin S) has been associated with increased RNA stability and markers of plaque progression and aortic aneurysm risk, although causality remains under investigation.
- Hypertension: A single edit in the FLNA gene (filamin A) can be sufficient to change an amino acid from glutamine to arginine. Mice lacking this specific edit demonstrate increased vascular contractility and diastolic hypertension.
- Heart failure (HF): Some studies report a global reduction in RNA editing in patients with HF, whereas others show mixed patterns, underscoring ongoing uncertainty, particularly regarding the formation of circular RNAs in the heart.
Translational Potential, Biomarkers, and RNA-Based Therapeutics
The present mini-review suggests that, because RNA editing levels in peripheral blood cells correlate strongly with those in heart tissue, the editing rate of genes such as IGFBP7 may serve as potential predictive biomarkers pending larger validation studies and clinical standardisation for heart failure.
The authors posit that techniques such as LEAPER 2.0 can recruit the body's own ADAR enzymes to repair specific genetic errors, thereby potentially offering reversible RNA-based alternatives to permanent DNA editing, such as CRISPR. Unlike the latter, RNA-based editing techniques are reversible and dose-controllable, which may reduce long-term genomic risks but still requires extensive clinical evaluation, theoretically allowing for "precision tuning" of heart function without the risk of permanent, off-target genomic changes.
Overall, while RNA editing represents a promising research frontier in cardiovascular biology, current evidence remains largely preclinical or associative, and further mechanistic and clinical validation is required before routine clinical translation.
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