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RNA editing of Filamin A pre‐ mRNA regulates vascular contraction and diastolic blood pressure
Author(s) -
Jain Mamta,
Mann Tomer D,
Stulić Maja,
Rao Shailaja P,
Kirsch Andrijana,
Pullirsch Dieter,
Strobl Xué,
Rath Claus,
Reissig Lukas,
Moreth Kristin,
KleinRodewald Tanja,
Bekeredjian Raffi,
GailusDurner Valerie,
Fuchs Helmut,
Hrabě de Angelis Martin,
Pablik Eleonore,
Cimatti Laura,
Martin David,
Zinnanti Jelena,
Graier Wolfgang F,
Sibilia Maria,
Frank Saša,
Leva Erez Y,
Jantsch Michael F
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201694813
Subject(s) - biology , library science , computer science
Epitranscriptomic events such as adenosine‐to‐inosine (A‐to‐I) RNA editing by ADAR can recode mRNA s 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.