title: Inhibition of miR-15 protects against cardiac ischemic injury.
abstract: BACKGROUND
  Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI.
  
  
  OBJECTIVE
  This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury.
  
  
  RESULTS
  Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI.
  
  
  CONCLUSIONS
  Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.
authors: miRagen Therapeutics, Inc, 6200 Lookout Rd, Boulder, CO 80301, USA.
authors: Thomas G
authors: TG
authors: Hullinger
authors: Rusty L
authors: RL
authors: Montgomery
authors: Anita G
authors: AG
authors: Seto
authors: Brent A
authors: BA
authors: Dickinson
authors: Hillary M
authors: HM
authors: Semus
authors: Joshua M
authors: JM
authors: Lynch
authors: Christina M
authors: CM
authors: Dalby
authors: Kathryn
authors: K
authors: Robinson
authors: Christianna
authors: C
authors: Stack
authors: Paul A
authors: PA
authors: Latimer
authors: Joshua M
authors: JM
authors: Hare
authors: Eric N
authors: EN
authors: Olson
authors: Eva
authors: E
authors: van Rooij
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000187:drug effects; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009841:Oligonucleotides / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine
chemical_list: D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; D009841:Oligonucleotides; C477371:locked nucleic acid