Selective blockade of microRNA-31-5p/calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia substrate

  1. Jasha Trompf*
  2. Kathryn Cox*
  3. Mohit Hulsurkar*
  4. Lucia M. Moreira
  5. Chi Him Kendrick Yiu
  6. Aaron M. Johnston
  7. Satadru K. Lahiri
  8. Shuai Zhao
  9. Paul Robinson
  10. Roddy Hiram
  11. Mozhdeh Mehdizadeh
  12. Lorena Perez Carrillo
  13. Rana Sayeed
  14. George Krasopoulos
  15. Vivek Srivastava
  16. Nicholas Walcot
  17. Shakil Farid
  18. Antonios Kourliouros
  19. Priya Sastry
  20. David A. Menassa
  21. Benjamin Davies
  22. Rita A. Schack
  23. Robia G. Pautler
  24. Keith M. Channon
  25. Craig Lygate
  26. Stanley Nattel
  27. Xander H. T. Wehrens
  28. Svetlana Reilly
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Abstract

Atrial fibrillation (AF), the commonest cardiac arrhythmia, is a major contributor to mortality and morbidity. Atrial tissue fibrosis, a hallmark of structural remodelling in AF, is currently incurable and significantly hinders AF-treatment. MicroRNA(miR)-31 is linked to ageing (a key risk factor for AF). Here, we show that AF-patients are characterised by upregulation of miR-31-5p in atrial cardiofibroblasts that negatively regulates the calcitonin receptor (CTR), thereby promoting atrial fibrogenesis and arrhythmia. Specific blockade of miR-31-5p/CTR-mRNA binding with LNA-miRNA-Target-Site-Blocker selectively increases atrial CTR expression and reverses advanced atrial fibrosis and arrhythmogenesis in vivo. These findings suggest a key role for miR-31-5p/CTR binding in promoting atrial fibrosis and arrhythmogenesis, and represents a first example of an RNA-based therapeutic capable of reversing established fibrosis that forms an AF substrate. *Jasha Trompf, Kathryn Cox, and Mohit Hulsurkar contributed equally to this work.

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