miR-25 Tough Decoy Enhances Cardiac Function in Heart Failure
| Autor: | Christine Wahlquist, Dongtak Jeong, Brian D. Brown, Mark Mercola, Roger J. Hajjar, Ahyoung Lee, Philyoung Lee, Jimeen Yoo, Sacha V. Kepreotis, Changwon Kho |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cardiac function curve Genetic enhancement Genetic Vectors MiRNA binding law.invention Sarcoplasmic Reticulum Calcium-Transporting ATPases 03 medical and health sciences law Drug Discovery Gene expression microRNA Gene Order Genetics Medicine Animals Humans RNA Messenger Molecular Biology Gene Library Pharmacology Heart Failure Base Sequence business.industry Antagomirs Dependovirus medicine.disease Myocardial Contraction Rats MicroRNAs 030104 developmental biology Gene Expression Regulation Heart failure Heart Function Tests Cancer research Molecular Medicine Suppressor Original Article RNA Interference business Decoy |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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