title: miR-223-IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach.
abstract: Pulmonary hypertension is a progressive disease with poor prognosis, characterized by pathological inward remodelling and loss of patency of the lung vasculature. The right ventricle is co-affected by pulmonary hypertension, which triggers events such as hypoxia and/or increased mechanical load. Initially the right ventricle responds with 'adaptive' hypertrophy, which is often rapidly followed by 'maladaptive' changes leading to right heart decompensation and failure, which is the ultimate cause of death.
  
  
  
  We report here that miR-223 is expressed in the murine lung and right ventricle at higher levels than in the left ventricle. Moreover, lung and right-ventricular miR-223 levels were markedly down-regulated by hypoxia. Correspondingly, increasing right-ventricular load by pulmonary artery banding, induced right-ventricular ischaemia, and the down-regulation of miR-223. Lung and right ventricle miR-223 down-regulation were linked with increased expression of the miR-223 target; insulin-like growth factor-I receptor (IGF-IR) and IGF-I downstream signalling. Similarly, miR-223 was decreased and IGF-IR increased in human pulmonary hypertension. Notably in young mice, miR-223 overexpression, the genetic inactivation or pharmacological inhibition of IGF-IR, all attenuated right-ventricular hypertrophy and improved right heart function under conditions of hypoxia or increased afterload.
  
  
  
  These findings highlight the early role of pulmonary and right-ventricular miR-223 and the IGF-IR in the right heart failure programme initiated by pulmonary hypoxia and increased mechanical load and may lead to the development of novel therapeutic strategies that target the development of PH and right heart failure.
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Frankfurt am Main, and German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany.
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Frankfurt am Main, and German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany.
authors.forename: Amro
authors.initials: A
authors.lastname: Elgheznawy
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Frankfurt am Main, and German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Popp
authors.affiliation: University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany.
authors.forename: Bhola Kumar
authors.initials: BK
authors.lastname: Dahal
authors.affiliation: University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Böhm
authors.affiliation: University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, Bad Nauheim, Germany.
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.affiliation: University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany.
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.affiliation: Institut für Herz- und Kreislaufphysiologie, Universitätsklinikum, Heinrich-Heine-Universität, Dusseldorf, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Gödecke
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, Germany German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jungmann
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, Germany German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, Germany German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Germany.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Frankfurt am Main, and German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Fisslthaler
authors.affiliation: University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, Bad Nauheim, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Frankfurt am Main, and German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany fleming@em.uni-frankfurt.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction; D018497:Ventricular Dysfunction, Right / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016278:Ventricular Function, Right
chemical_list: C000607695:GSK1904529A; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000597236:IGF1R protein, human; D007093:Imidazoles; C531907:MIRN122 microRNA, human; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; D011725:Pyridines; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1
keywords: Hypertension; Hypoxia; Pulmonary; Pulmonary heart disease