title: Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice.
abstract: 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. MicroRNAs 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.
  
  
  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/miRNA 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 miRNA therapy in a transgenic model of severe, chronic MD-associated DCM.
authors: Translational Cardiomyology Lab, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors: Mattia
authors: M
authors: Quattrocelli
authors: Stefania
authors: S
authors: Crippa
authors: Celeste
authors: C
authors: Montecchiani
authors: Jordi
authors: J
authors: Camps
authors: Antonia Icaro
authors: AI
authors: Cornaglia
authors: Luisa
authors: L
authors: Boldrin
authors: Jennifer
authors: J
authors: Morgan
authors: Alberto
authors: A
authors: Calligaro
authors: Andrea
authors: A
authors: Casasco
authors: Aldo
authors: A
authors: Orlacchio
authors: Rik
authors: R
authors: Gijsbers
authors: Jan
authors: J
authors: D'Hooge
authors: Jaan
authors: J
authors: Toelen
authors: Stefan
authors: S
authors: Janssens
authors: Maurilio
authors: M
authors: Sampaolesi
mesh_terms: D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002908:Chronic Disease; D000229:Dependovirus; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020127:Recovery of Function; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D035683:MicroRNAs; D049031:Sarcoglycans; D009320:Atrial Natriuretic Factor
keywords: cardiomyopathy; miRNA therapy; microRNAs; muscular dystrophy
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