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

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

doi:10.15252/embj.201694813

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.

Highlights

Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent epitranscriptomic change in mammalian RNAs (Nishikura, 2010)
Filamin A (FLNA) editing is highest in cardiovascular tissue and significantly reduced in patients with cardiac disease mRNA recoding by ADAR2 is typically a brain-specific phenomenon that can diversify receptor function (Holmgren & Rosenthal, 2015)
ADAR2 is thought to act mainly in the brain, and its clinical significance has far been linked to nervous systemrelated functions such as AMPA receptor editing, which, if disturbed, leads to intractable seizures and death

Summary

Introduction

Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent epitranscriptomic change in mammalian RNAs (Nishikura, 2010). A-to-I editing is catalyzed by adenosine deaminases acting on RNA (ADAR) that recognize double-stranded and structured RNAs (Nishikura, 2010). ADAR1 is expressed in all tissues and likely targets repeat-derived double-stranded (ds) RNAs. In contrast, ADAR2 shows its highest expression in the brain and can edit coding and non-coding regions of mRNAs (Riedmann et al, 2008; Nishikura, 2010). Most mammalian recoding edits known today affect mRNAs encoding ion channels and receptors within the central nervous system (Hoopengardner et al, 2003; Savva et al, 2012; Li & Church, 2013).

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