Inhibition of microRNA-92a protects against ischemia/reperfusion injury in a large-animal model

Rabea Hinkel, Daniela Penzkofer, Stefanie Zühlke, Ariane Fischer, Wira Husada, Quan-Fu Xu, Elisabeth Baloch, Eva van Rooij, Andreas M Zeiher, Christian Kupatt, Stefanie Dimmeler

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

BACKGROUND: MicroRNAs (miRs) are small noncoding RNAs that posttranscriptionally control gene expression. Small-animal studies suggest that miRs might offer novel therapeutic targets in cardiovascular diseases such as cardioprotection of murine hearts after myocardial infarction via miR-92a inhibitors. Because the functional benefits of miR-92a inhibitors in larger preclinical models are not known, we assessed the therapeutic efficacy of miR-92a inhibition in a porcine model of ischemia and reperfusion.

METHODS AND RESULTS: Pigs (n=5 per group) underwent percutaneous ischemia/reperfusion (60 min/72 h or 7 days, respectively). Locked nucleic acid-modified antisense miR-92a (LNA-92a) was applied either regionally (antegrade or retrograde) with a catheter or systemically (intravenously). LNA-92a significantly (P<0.01) reduced miR-92a expression in the infarct zone regardless of the application venue. However, catheter-based delivery, but not intravenous infusion, of LNA-92a significantly (P<0.05) reduced the infarct size compared with control LNA-treated pigs, which correlated with an improved ejection fraction and left ventricular end-diastolic pressure (P<0.05). Histochemistry revealed that LNA-92a increased capillary density but decreased leukocyte influx and cardiac cell death. Complete loss of miR-92a in mice attenuated the infarct-related myocardial dysfunction to a larger extent than cardiomyocyte-specific miR-92a deletion. In vitro, LNA-92a protected against hypoxia/reoxygenation-induced cardiomyocyte cell death.

CONCLUSIONS: Regional LNA-92a delivery reduces miR-92a levels and infarct size and postischemic loss of function. LNA-92a exerts cell-protective, proangiogenic, and anti-inflammatory effects. miR-92a inhibition might be a novel therapeutic tool to preserve cardiac function after ischemia.

Original languageEnglish
Pages (from-to)1066-75
Number of pages10
JournalCirculation
Volume128
Issue number10
DOIs
Publication statusPublished - 03 Sep 2013

Keywords

  • Animals
  • Cardiotonic Agents
  • Disease Models, Animal
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • MicroRNAs
  • Myocardial Infarction
  • Myocardial Reperfusion Injury
  • Oligonucleotides, Antisense
  • Swine

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