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 language | English |
|---|---|
| Article number | e94813 |
| Journal | EMBO Journal |
| Volume | 37 |
| Issue number | 19 |
| DOIs | |
| State | Published - 1 Oct 2018 |
Bibliographical note
Publisher Copyright:© 2018 The Authors. Published under the terms of the CC BY 4.0 license
Funding
The authors would like to thank Lena Hirtler for supervising human tissue isolation. We thank the VBCF preclinical phenotyping facility, Sylvia Badurek, and Mumna Al Banchaabouchi for mouse blood pressure measurement, Jelena Zinnanti for MRI imaging, and the MFPL mass spectrometry facility for mass spectrometry analysis. Irmgard Fischer and Ingrid Hammer are thanked for help with sectioning and staining of mouse tissues. Michael Janisiw and Peter Burg are thanked for their excellent technical assistance. We thank Thomas Nardelli for help with preparation with graphics. Margarete Lechleitner is acknowledged for help with myography experiments. The German Mouse Clinic team is thanked for thorough phenotyping of mice. We thank Life Science Editors for technical, editing assistance. This work was supported through grant numbers F4313, P22956, and P27166-B23 of the Austrian Science Foundation to MFJ and SF, respectively. M. Stulic was supported through the Austrian Science Foundation Doctoral Program W1207. LC was supported by the Mahlke-Obermann Stiftung and the European Union's Seventh Framework Programme (FP7) Marie Curie Actions (Grant Agreement No. 609431)/INDICAR—Interdisciplinary Cancer Research. M. Sibilia was funded by the EC programs QLG1-CT-2001-00869 and LSHC-CT-2006-037731 (Growthstop), the Austrian Federal Government's GEN-AU program “Austromouse” (GZ 200.147/1-VI/1a/2006), and the Austrian Science Fund grants FWF-P18421, FWF-P18782, SFB-23-B13, and DK W1212. EYL was supported by the European Research Council (311257) and the Israel Science Foundation (1380/14). In addition, the study was partially funded by the German Federal Ministry of Education and Research to the GMC (Infrafrontier Grant 01KX1012). The authors would like to thank Lena Hirtler for supervising human tissue isolation. We thank the VBCF preclinical phenotyping facility, Sylvia Badurek, and Mumna Al Banchaabouchi for mouse blood pressure measurement, Jelena Zinnanti for MRI imaging, and the MFPL mass spectrometry facility for mass spectrometry analysis. Irmgard Fischer and Ingrid Hammer are thanked for help with sectioning and staining of mouse tissues. Michael Janisiw and Peter Burg are thanked for their excellent technical assistance. We thank Thomas Nardelli for help with preparation with graphics. Margarete Lechleitner is acknowledged for help with myography experiments. The German Mouse Clinic team is thanked for thorough phenotyping of mice. We thank Life Science Editors for technical, editing assistance. This work was supported through grant numbers F4313, P22956, and P27166-B23 of the Austrian Science Foundation to MFJ and SF, respectively. M. Stulic was supported through the Austrian Science Foundation Doctoral Program W1207. LC was supported by the Mahlke-Obermann Stiftung and the European Union’s Seventh Framework Programme (FP7) Marie Curie Actions (Grant Agreement No. 609431)/INDICAR —Interdisciplinary Cancer Research. M. Sibilia was funded by the EC programs QLG1-CT-2001-00869 and LSHC-CT-2006-037731 (Growthstop), the Austrian Federal Government’s GEN-AU program “Austromouse” (GZ 200.147/1-VI/1a/ 2006), and the Austrian Science Fund grants FWF-P18421, FWF-P18782, SFB-23-B13, and DK W1212. EYL was supported by the European Research Council (311257) and the Israel Science Foundation (1380/14). In addition, the study was partially funded by the German Federal Ministry of Education and Research to the GMC (Infrafrontier Grant 01KX1012).
| Funders | Funder number |
|---|---|
| Austrian Federal Government's GEN-AU | |
| Austrian Federal Government’s GEN-AU | GZ 200.147/1-VI/1a/ 2006 |
| FP7) Marie Curie Actions | |
| German Mouse Clinic | P22956, F4313, P27166-B23 |
| INDICAR | |
| Mahlke-Obermann Stiftung | |
| Seventh Framework Programme | 311257, 609431 |
| General Medical Council | 01KX1012 |
| European Commission | LSHC-CT-2006-037731, QLG1-CT-2001-00869 |
| European Commission | |
| Bundesministerium für Bildung und Forschung | |
| Austrian Science Fund | FWF-P18782, SFB-23-B13, FWF-P18421, W1207, DK W1212 |
| Israel Science Foundation | 1380/14 |
| Seventh Framework Programme |
Keywords
- Filamin A (FLNA)
- RNA editing
- adenosine deaminases acting on RNA (ADAR)
- cardiovascular disease
- hypertension
