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AntimiR-21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury.
- Source :
-
Journal of the American College of Cardiology [J Am Coll Cardiol] 2020 Apr 21; Vol. 75 (15), pp. 1788-1800. - Publication Year :
- 2020
-
Abstract
- Background: miR-21 is a central regulator of cardiac fibrosis, and its inhibition in small-animal models has been shown to be an effective antifibrotic strategy in various organs, including the heart. Effective delivery of therapeutic antisense micro-ribonucleic acid (antimiR) molecules to the myocardium in larger organisms is challenging, though, and remains to be established for models of chronic heart failure.<br />Objectives: The aims of this study were to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a pig model of heart failure and determine its effect on the cardiac transcriptomic signature and cellular composition.<br />Methods: Pigs underwent transient percutaneous occlusion of the left coronary artery and were followed up for 33 days. AntimiR-21 (10 mg) was applied by intracoronary infusion at days 5 and 19 after the injury. Cardiac function was assessed in vivo, followed by histological analyses and deep ribonucleic acid sequencing (RNA-seq) of the myocardium and genetic deconvolution analysis.<br />Results: AntimiR-21 effectively suppressed the remodeling-associated increase of miR-21. At 33 days after ischemia/reperfusion injury, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy and improved cardiac function. Deep RNA-seq revealed a significant derepression of the miR-21 targetome in antimiR-21-treated myocardium and a suppression of the inflammatory response and mitogen-activated protein kinase signaling. A genetic deconvolution approach built on deep RNA-seq and single-cell RNA-seq data identified reductions in macrophage and fibroblast numbers as the key cell types affected by antimiR-21 treatment.<br />Conclusions: This study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of heart failure.<br /> (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cardiomegaly genetics
Disease Models, Animal
Fibroblasts metabolism
Fibrosis genetics
Macrophages metabolism
Mitogen-Activated Protein Kinases
Oligonucleotides chemistry
Cardiomegaly therapy
Fibrosis therapy
MicroRNAs antagonists & inhibitors
Myocardium pathology
Reperfusion Injury therapy
Ventricular Remodeling genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-3597
- Volume :
- 75
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of the American College of Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 32299591
- Full Text :
- https://doi.org/10.1016/j.jacc.2020.02.041