University of Oxford, UK
Svetlana Reilly is a Research fellow at University of Oxford. Dr. Svetlana Reilly is a postdoc with Prof. Barbara Casadei in Cardiovascular Medicine, won the Young Research Worker Prize at the 2013 British Cardiovascular Society annual meeting. Dr. Svetlana Reilly has done completed her education from Medical academy, Russia.
Objectives - Atrial fibrillation (AF) is a growing public health burden and its treatment remains a challenge. AF leads to electrical remodelling of the atria, which, in turn, promotes AF maintenance and resistance to treatment. Although remodelling has long been a therapeutic target in AF, its causes remain poorly understood. Methods and findings – Using atrial samples from 259 patients (51 with permanent AF) and 36 goats (24 with AF), we show that atrial-specific upregulation of microRNA-31 (miR31) in goat and human AF causes dystrophin [DYS] translational repression and accelerates mRNA degradation of neuronal nitric oxide synthase [nNOS] leading to a profound reduction in atrial DYS and nitric oxide availability. Prediction algorithms and reporter assays established DYS and nNOS as miR31 targets. In actinomycin D-treated myocytes from patients in sinus rhythm, miR31 accelerated nNOS (but not DYS) mRNA decay. Physical interaction between miR31 and DYS or nNOS within the RNA induced silencing complex [RISC] in atrial myocytes from patients with AF [hAFm] was confirmed by immunoprecipitation of Argonaut 2. MiR31 overexpression and/or disruption of nNOS signaling (with nNOS-siRNA or secondary to nNOS gene deletion) recapitulates hallmark features of AF-induced remodelling (shortening of action potential duration [APD] and loss of APD rate-dependency) and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in hAFm restores dystrophin and nNOS and normalizes atrial electrical properties. Masking miR31 binding site on the DYS increases both DYS and nNOS protein (but not mRNA), in keeping with a stabilising effect of DYS on nNOS protein. Indeed, K48-linked polyubiquitination and proteasomal degradation of nNOS were increased in hAFm. Interpretation - Atrial-specific upregulation of miR-31 in human AF is a key mechanism causing atrial dystrophin and nNOS depletion, which, in turn, contributes to the atrial phenotype begetting this arrhythmia.