AntimiR-21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury

J Am Coll Cardiol. 2020 Apr 21;75(15):1788-1800. doi: 10.1016/j.jacc.2020.02.041.

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.

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.

Keywords: cardiac disease; fibrosis; miR-21; microRNA; porcine model of heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / therapy*
  • Disease Models, Animal
  • Fibroblasts / metabolism
  • Fibrosis / genetics
  • Fibrosis / therapy*
  • Macrophages / metabolism
  • MicroRNAs / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases
  • Myocardium / pathology*
  • Oligonucleotides / chemistry
  • Reperfusion Injury / therapy*
  • Ventricular Remodeling* / genetics

Substances

  • MIRN21 microRNA, human
  • MicroRNAs
  • Oligonucleotides
  • locked nucleic acid
  • Mitogen-Activated Protein Kinases