Open AccessLong‐Term miR‐669a Therapy Alleviates Chronic Dilated Cardiomyopathy in Dystrophic Mice
Author(s) -
Quattrocelli Mattia,
Crippa Stefania,
Montecchiani Celeste,
Camps Jordi,
Cornaglia Antonia Icaro,
Boldrin Luisa,
Morgan Jennifer,
Calligaro Alberto,
Casasco Andrea,
Orlacchio Aldo,
Gijsbers Rik,
D'Hooge Jan,
Toelen Jaan,
Janssens Stefan,
Sampaolesi Maurilio
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000284
Subject(s) - medicine , dilated cardiomyopathy , cardiomyopathy , cardiology , heart failure
Background Dilated cardiomyopathy ( DCM ) is a leading cause of chronic morbidity and mortality in muscular dystrophy ( MD ) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. Micro RNA s have been implicated as fine regulators of cardiomyopathic progression. Previously, miR‐669a downregulation has been linked to the severe DCM progression displayed by Sgcb ‐null dystrophic mice. However, the impact of long‐term overexpression of miR‐669a on muscle structure and functionality of the dystrophic heart is yet unknown. Methods and Results Here, we demonstrate that intraventricular delivery of adeno‐associated viral (AAV) vectors induces long‐term (18 months) miR‐669a overexpression and improves survival of Sgcb ‐null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR‐669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/mi RNA profile of DCM markers. Furthermore, long‐term miR‐669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. Conclusions Our findings provide the first evidence of long‐term beneficial impact of AAV ‐mediated mi RNA therapy in a transgenic model of severe, chronic MD ‐associated DCM .