Long‐Term
            <i>miR‐669a</i>
            Therapy Alleviates Chronic Dilated Cardiomyopathy in Dystrophic Mice

Quattrocelli, Mattia; Crippa, Stefania; Montecchiani, Celeste; Cornaglia, Antonia Icaro; Boldrin, Luisa; Morgan, Jennifer E.; Calligaro, Alberto; Casasco, Andrea; Orlacchio, Aldo; Gijsbers, Rik; D'hooge, Jan; Toelen, Jaan; Janssens, Stefan; Sampaolesi, Maurilio

doi:10.1161/jaha.113.000284

Cited by 62 publications

(50 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recently, another group has shown that miR-486 is a direct target of myostatin signaling, and that genetic ablation of myostatin induces myotube hypertrophy via miR-486 and PTEN/AKT signaling (100). Several groups have shown that overexpression of muscle microRNAs can ameliorate some pathological signs of muscle disease in murine models (101,102). One can envision that miR-486 overexpression via adeno-associated virus (AAV) might have beneficial effects on dystrophin-defective muscles by promoting muscle hypertrophy and promoting regeneration (103).…”

Section: Dock3 Is An Essential Regulator Of Pten/akt and Rac1 Signalimentioning

confidence: 99%

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Alexander¹,

Casar²,

Matsuki³

et al. 2014

J. Clin. Invest.

126

122

View full text Add to dashboard Cite

Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which resultsin dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmd mdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmd mdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle-specific miR-486 overexpression in Dmd mdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle.

show abstract

Section: Dock3 Is An Essential Regulator Of Pten/akt and Rac1 Signalimentioning

confidence: 99%

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Alexander¹,

Casar²,

Matsuki³

et al. 2014

J. Clin. Invest.

126

122

View full text Add to dashboard Cite

show abstract

“…73 Other reports indicate that AAV9-microRNA378 attenuates cardiac hypertrophy after pressure overload because of thoracic aortic constriction 74 and that AAV9-microRNA-669a alleviates chronic dilated cardiomyopathy in dystrophic mice. 75 …”

Section: In Vivo Cardiac Expression Of Small Rnas Using Aav Vectorsmentioning

confidence: 99%

Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

Zacchigna

Zentilin

Giacca

2014

Circulation Research

119

View full text Add to dashboard Cite

Abstract:The use of vectors based on the small parvovirus adeno-associated virus has gained significant momentum during the past decade. Their high efficiency of transduction of postmitotic tissues in vivo, such as heart, brain, and retina, renders these vectors extremely attractive for several gene therapy applications affecting these organs. Besides functional correction of different monogenic diseases, the possibility to drive efficient and persistent transgene expression in the heart offers the possibility to develop innovative therapies for prevalent conditions, such as ischemic cardiomyopathy and heart failure. Therapeutic genes are not only restricted to protein-coding complementary DNAs but also include short hairpin RNAs and microRNA genes, thus broadening the spectrum of possible applications. In addition, several spontaneous or engineered variants in the virus capsid have recently improved vector efficiency and expanded their tropism. Apart from their therapeutic potential, adeno-associated virus vectors also represent outstanding investigational tools to explore the function of individual genes or gene combinations in vivo, thus providing information that is conceptually similar to that obtained from genetically modified animals. Finally, their single-stranded DNA genome can drive homology-directed gene repair at high efficiency. Here, we review the main molecular characteristics of adeno-associated virus vectors, with a particular view to their applications in the cardiovascular field.

show abstract

“…Sarcomere organization improved with reduced ventricular atrial natriuretic peptide and improved molecular markers of dilated cardiomyopathy. Increases in fractional shortening were also observed on long-term treatment of these mice (22). Such direct implication of miRNA-targeted therapeutic benefit brings hope to this area of investigation.…”

Section: Dilated Cardiomyopathymentioning

confidence: 79%

MicroRNAs as therapeutic targets in cardiomyopathies: myth or reality?

Nair

Góngora

2014

Biomolecular Concepts

View full text Add to dashboard Cite

Abstract:The identification of biomarkers for cardiomyopathy presents a distinct challenge as the etiologies are widely varied. The discovery of small non-coding miRNAs with gene regulatory function has opened new avenues of investigation in basic and clinical sciences. The search for regulatory nucleotide sequences that have specific gene targets have put miRNAs at the forefront of development of therapeutics, and may serve as valuable diagnostic and/or therapeutic targets. MiRNAs appear to influence both positive and negative remodeling. As cardiac remodeling is a complex process, global molecular networks and miRNA profiles may be required to fulfill the roles of macroregulators. The type of cardiomyopathy leading to heart failure in the long run appears to have a distinct molecular pattern underlying the pathophysiology. This review discusses in brief the existing literature on the molecular signatures in dilated, ischemic, hypertrophic, stress, and peripartum cardiomyopathies that may be used to target therapies for specific etiologies once diagnosed, therefore exploring the utility of specific miRNAs in tailoring therapy for heart failure based on etiology.

show abstract

Long‐Term miR‐669a Therapy Alleviates Chronic Dilated Cardiomyopathy in Dystrophic Mice

Cited by 62 publications

References 48 publications

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

MicroRNAs as therapeutic targets in cardiomyopathies: myth or reality?

Contact Info

Product

Resources

About