Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase

Svetlana N. Reilly*, Xing Liu, Ricardo Carnicer, Alice Recalde, Anna Muszkiewicz, Raja Jayaram, Maria Cristina Carena, Rohan Wijesurendra, Matilde Stefanini, Nicoletta C. Surdo, Oliver Lomas, Chandana Ratnatunga, Rana Sayeed, George Krasopoulos, Timothy Rajakumar, Alfonso Bueno-Orovio, Sander Verheule, Tudor A. Fulga, Blanca Rodriguez, Ulrich SchottenBarbara Casadei*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Article number340ra74
JournalScience Translational Medicine
Issue number340
Publication statusPublished - 25 May 2016

Cite this