Svetlana Reilly
University of Oxford, UK
Title: Atrial-specific upregulation of microRNA-31 depletes dystrophin and neuronal nitric oxide synthase (nNOS), and leads to electrical remodelling in human atrial fibrillation
Biography
Biography: Svetlana Reilly
Abstract
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.