title: Inhibition of microRNA-92a protects against ischemia/reperfusion injury in a large-animal model.
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.
  
  
  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.
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum Großhadern, and German Center for Cardiovascular Research-Munich Heart Alliance, Marchioninistrasse 15, Munich, Germany. rabea.hinkel@med.uni-muenchen.de
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Daniela
authors.initials: D
authors.lastname: Penzkofer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zühlke
authors.forename: Ariane
authors.initials: A
authors.lastname: Fischer
authors.forename: Wira
authors.initials: W
authors.lastname: Husada
authors.forename: Quan-Fu
authors.initials: QF
authors.lastname: Xu
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Baloch
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense
keywords: apoptosis; infarction; inflammation; ischemia; microRNAs; reperfusion