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Titel
RNA editing of Filamin A pre-mRNA regulates vascular contraction and diastolic blood pressure
Verfasser / VerfasserinJantsch, Michael F. ; Jain, Mamta ; Mann, Tomer D. ; Stulic, Maja ; Rao, Shailaja P. ; Kirsch, Andrijana ; Pullirsch, Dieter ; Strobl, Xúe ; Rath, Claus ; Reissig, Lukas ; Moreth, Kristin ; Klein-Rodewald, Tanja ; Bekeredijan, Raffi ; Gailus-Durner, Valerie ; Fuchs, Helmut ; Hrabe de Angelis, Martin ; Pablik, Eleonore ; Cimatti, Laura ; Martin, David ; Zinnanti, Jelena ; Graier, Wolfgang F. ; Sibilia, Maria ; Frank, Sasa ; Levanon, Erez Y.
Erschienen in
The EMBO Journal, 2018, Jg. 37, H. 19, e94813
ErschienenWiley-Blackwell, 2018
SpracheEnglisch
DokumenttypAufsatz in einer Zeitschrift
Schlagwörter (EN)adenosine deaminases acting on RNA (ADAR) / cardiovascular disease / Filamin A (FLNA) / hypertension / RNA editing
URNurn:nbn:at:at-ubmuw:3-671 Persistent Identifier (URN)
DOI10.15252/embj.201694813 
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RNA editing of Filamin A pre-mRNA regulates vascular contraction and diastolic blood pressure [2.08 mb]
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Zusammenfassung (Englisch)

Epitranscriptomic events such as adenosinetoinosine (AtoI) 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 QtoR transition in the interactive Cterminal 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. Patientderived RNASeq 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.

Synopsis

RNAediting of Filamin A premRNA is decreased in human cardiac disease. A mouse model lacking this editing site shows altered smooth muscle contraction and diastolic blood pressure, illustrating that ADAR2dependent RNA editing plays a functional role outside the central nervous system.

The Filamin A (FLNA) premRNA is subject to RNA editing with the highest rates seen in the cardiovascular system.

FLNA editing rates are reduced in cardiovascular disease patients.

In mice, FLNA editing controls smooth muscle contraction of the dorsal aorta.

Mice deficient in FLNA editing show elevated diastolic blood pressure and cardiac remodeling.

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CC-BY-Lizenz (4.0)Creative Commons Namensnennung 4.0 International Lizenz