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

Epitranscriptomic events like Adenosine to Inosine (A-I) RNA editing by ADARs can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin cross-linking protein Filamin A (FLNA) mediates a Q-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 remodelling and reduced systolic output. These results demonstrate a causal relationship between RNA-editing and the development of cardiovascular disease demonstrating that a single epitranscriptomic RNA modification can maintain cardiovascular health.