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Published on: March 12, 2018
AntimiR-21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury
Rabea Hinkel1, Deepak Ramanujam2, Veronika Kaczmarek3
11. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; Institute for Cardiovascular Prevention, Ludwigs-Maximilians-Universität München, Munich, Germany; Deutsches Primatenzentrum GmbH, Leibnitz-Institut für Primatenforschung, Laboratory Animal Science Unit, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
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.
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.
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.
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.
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.
