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

Mamta Jain, Tomer D. Mann, Maja Stulić, Shailaja P. Rao, Andrijana Kirsch, Dieter Pullirsch, Xué Strobl, Claus Rath, Lukas Reissig, Kristin Moreth, Tanja Klein-Rodewald, Raffi Bekeredjian, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Eleonore Pablik, Laura Cimatti, David Martin, Jelena Zinnanti, Wolfgang F. GraierMaria Sibilia, Saša Frank, Erez Y. Levanon, Michael F. Jantsch

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere94813
JournalEMBO Journal
Volume37
Issue number19
DOIs
StatePublished - 1 Oct 2018

Keywords

  • Filamin A (FLNA)
  • RNA editing
  • adenosine deaminases acting on RNA (ADAR)
  • cardiovascular disease
  • hypertension

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