title: AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension.
abstract: OBJECTIVE
  Dysregulation of the bone morphogenetic protein receptor type 2 (BMPR2) is a hallmark feature that has been described in several forms of pulmonary hypertension. We recently identified the microRNA miR-20a within a highly conserved pathway as a regulator of the expression of BMPR2. To address the pathophysiological relevance of this pathway in vivo, we employed antagomiR-20a and investigated whether specific inhibition of miR-20a could restore functional levels of BMPR2 and, in turn, might prevent pulmonary arterial vascular remodelling.
  
  
  RESULTS
  For specific inhibition of miR-20a, cholesterol-modified RNA oligonucleotides (antagomiR-20a) were synthesized. The experiments in mice were performed by using the hypoxia-induced mouse model for pulmonary hypertension and animal tissues were analysed for right ventricular hypertrophy and pulmonary arterial vascular remodelling. Treatment with antagomiR-20a enhanced the expression levels of BMPR2 in lung tissues; moreover, antagomiR-20a significantly reduced wall thickness and luminal occlusion of small pulmonary arteries and reduced right ventricular hypertrophy. To assess BMPR2 signalling and proliferation, we performed in vitro experiments with human pulmonary arterial smooth muscle cells (HPASMCs). Transfection of HPASMCs with antagomiR-20a resulted in activation of downstream targets of BMPR2 showing increased activation of Id-1 and Id-2. Proliferation of HPASMCs was found to be reduced upon transfection with antagomiR-20a.
  
  
  CONCLUSIONS
  This is the first report showing that miR-20a can be specifically targeted in an in vivo model for pulmonary hypertension. Our data emphasize that treatment with antagomiR-20a restores functional levels of BMPR2 in pulmonary arteries and prevents the development of vascular remodelling.
authors.affiliation: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology (ZIHP) University Zurich, University Hospital Zurich, Gloriastrasse 23, CH-8091 Zurich, Switzerland Pulmonary Hypertension Working Group, University Hospital Zurich, Zurich, Switzerland matthias.brock@usz.ch.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brock
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center of Integrative Human Physiology (ZIHP), University Zurich, Zurich, Switzerland.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Samillan
authors.affiliation: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology (ZIHP) University Zurich, University Hospital Zurich, Gloriastrasse 23, CH-8091 Zurich, Switzerland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Trenkmann
authors.affiliation: Equine Department, Vetsuisse Faculty, University Zurich, Zurich, Switzerland.
authors.forename: Colin
authors.initials: C
authors.lastname: Schwarzwald
authors.affiliation: Pulmonary Hypertension Working Group, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ulrich
authors.affiliation: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology (ZIHP) University Zurich, University Hospital Zurich, Gloriastrasse 23, CH-8091 Zurich, Switzerland.
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center of Integrative Human Physiology (ZIHP), University Zurich, Zurich, Switzerland.
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center of Integrative Human Physiology (ZIHP), University Zurich, Zurich, Switzerland.
authors.forename: Louise
authors.initials: L
authors.lastname: Ostergaard
authors.affiliation: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology (ZIHP) University Zurich, University Hospital Zurich, Gloriastrasse 23, CH-8091 Zurich, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.affiliation: Pulmonary Hypertension Working Group, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Speich
authors.affiliation: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology (ZIHP) University Zurich, University Hospital Zurich, Gloriastrasse 23, CH-8091 Zurich, Switzerland Pulmonary Hypertension Working Group, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Huber
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002784:Cholesterol / Q000031:analogs & derivatives / Q000494:pharmacology; D003326:Coronary Circulation / Q000502:physiology; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009843:Oligoribonucleotides / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D035683:MicroRNAs; C532375:Mirn20 microRNA, mouse; D009843:Oligoribonucleotides; D002784:Cholesterol; D052006:Bone Morphogenetic Protein Receptors, Type II