miR-25 Tough Decoy Enhances Cardiac Function in Heart Failure.

Autor:	Jeong D; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Yoo J; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Lee P; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Kepreotis SV; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Lee A; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Wahlquist C; Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA 94304, USA., Brown BD; Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Kho C; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Mercola M; Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA 94304, USA., Hajjar RJ; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: roger.hajjar@mssm.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2018 Mar 07; Vol. 26 (3), pp. 718-729. Date of Electronic Publication: 2017 Nov 26.
DOI:	10.1016/j.ymthe.2017.11.014
Abstrakt:	MicroRNAs are promising therapeutic targets, because their inhibition has the potential to normalize gene expression in diseased states. Recently, our group found that miR-25 is a key SERCA2a regulating microRNA, and we showed that multiple injections of antagomirs against miR-25 enhance cardiac contractility and function through SERCA2a restoration in a murine heart failure model. However, for clinical application, a more stable suppressor of miR-25 would be desirable. Tough Decoy (TuD) inhibitors are emerging as a highly effective method for microRNA inhibition due to their resistance to endonucleolytic degradation, high miRNA binding affinity, and efficient delivery. We generated a miR-25 TuD inhibitor and subcloned it into a cardiotropic AAV9 vector to evaluate its efficacy. The AAV9 TuD showed selective inhibition of miR-25 in vitro cardiomyoblast culture. In vivo, AAV9-miR-25 TuD delivered to the murine pressure-overload heart failure model selectively decreased expression of miR-25, increased levels of SERCA2a protein, and ameliorated cardiac dysfunction and fibrosis. Our data indicate that miR-25 TuD is an effective long-term suppressor of miR-25 and a promising therapeutic candidate to treat heart failure. (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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