title: Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase.
abstract: Atrial fibrillation (AF) is a growing public health burden, and its treatment remains a challenge. AF leads to electrical remodeling of the atria, which in turn promotes AF maintenance and resistance to treatment. Although remodeling has long been a therapeutic target in AF, its causes remain poorly understood. We show that atrial-specific up-regulation of microRNA-31 (miR-31) in goat and human AF depletes neuronal nitric oxide synthase (nNOS) by accelerating mRNA decay and alters nNOS subcellular localization by repressing dystrophin translation. By shortening action potential duration and abolishing rate-dependent adaptation of the action potential duration, miR-31 overexpression and/or disruption of nNOS signaling recapitulates features of AF-induced remodeling and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in atrial myocytes from patients with AF restores dystrophin and nNOS and normalizes action potential duration and its rate dependency. These findings identify atrial-specific up-regulation of miR-31 in human AF as a key mechanism causing atrial dystrophin and nNOS depletion, which in turn contributes to the atrial phenotype begetting this arrhythmia. miR-31 may therefore represent a potential therapeutic target in AF.
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Reilly
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Carnicer
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Recalde
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Muszkiewicz
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Raja
authors.initials: R
authors.lastname: Jayaram
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Carena
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Rohan
authors.initials: R
authors.lastname: Wijesurendra
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Stefanini
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Nicoletta C
authors.initials: NC
authors.lastname: Surdo
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lomas
authors.affiliation: Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Chandana
authors.initials: C
authors.lastname: Ratnatunga
authors.affiliation: Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Rana
authors.initials: R
authors.lastname: Sayeed
authors.affiliation: Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: George
authors.initials: G
authors.lastname: Krasopoulos
authors.affiliation: Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rajakumar
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bueno-Orovio
authors.affiliation: Department of Physiology, University of Maastricht, 6211 LK Maastricht, Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.affiliation: Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Tudor A
authors.initials: TA
authors.lastname: Fulga
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Department of Physiology, University of Maastricht, 6211 LK Maastricht, Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D001281:Atrial Fibrillation / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism*; D005786:Gene Expression Regulation; D006041:Goats; D006325:Heart Atria / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016189:Dystrophin; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D052248:Nitric Oxide Synthase Type I