title: Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension.
abstract: BACKGROUND
  MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in experimental pulmonary hypertension (PH).
  
  
  OBJECTIVE
  To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH.
  
  
  METHODS
  We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells.
  
  
  RESULTS
  In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotaline-induced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells.
  
  
  CONCLUSIONS
  Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, Bad Nauheim, Germany.
authors.forename: Soni S
authors.initials: SS
authors.lastname: Pullamsetti
authors.forename: Carmen
authors.initials: C
authors.lastname: Doebele
authors.forename: Ariane
authors.initials: A
authors.lastname: Fischer
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.forename: Bhola K
authors.initials: BK
authors.lastname: Dahal
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Angelika
authors.initials: A
authors.lastname: Bonauer
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D000070416:Antagomirs; D015153:Blotting, Western; D002302:Cardiac Output / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D009843:Oligoribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014655:Vascular Resistance / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects
chemical_list: D000070416:Antagomirs; C524941:MIRN17 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C541873:Mirn92 microRNA, mouse; D009843:Oligoribonucleotides; C541876:antagomir-92a