Selective blockade of microRNA-31-5p/calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia substrate.
Trompf J., Cox K., Hulsurkar M., Moreira LM., Yiu CHK., Johnston AM., Lahiri SK., Zhao S., Robinson P., Hiram R., Mehdizadeh M., Carrillo LP., Sayeed R., Krasopoulos G., Srivastava V., Walcot N., Farid S., Kourliouros A., Sastry P., Menassa DA., Davies B., Schack RA., Pautler RG., Channon KM., Lygate C., Nattel S., Wehrens XHT., Reilly S.
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.