title: MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD.
abstract: Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNA-target interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD.
  
  
  
  Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1β and tumor necrosis factor-α. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients.
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Caroline
authors: C
authors: Leuenberger
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.|Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland.
authors: Claudio
authors: C
authors: Schuoler
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Hannah
authors: H
authors: Bye
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Célia
authors: C
authors: Mignan
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Thomas
authors: T
authors: Rechsteiner
authors: Division of Thoracic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Sven
authors: S
authors: Hillinger
authors: Division of Thoracic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Isabelle
authors: I
authors: Opitz
authors: Faculty of Biology and Medicine, Service de Pneumologie, University of Lausanne, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Benjamin
authors: B
authors: Marsland
authors: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Alen
authors: A
authors: Faiz
authors: Department of Pulmonary Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Pieter S
authors: PS
authors: Hiemstra
authors: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Wim
authors: W
authors: Timens
authors: Center for Molecular Cardiology, Division of Cardiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors: Giovanni G
authors: GG
authors: Camici
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Malcolm
authors: M
authors: Kohler
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Lars C
authors: LC
authors: Huber
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. matthias.brock@usz.ch.
authors: Matthias
authors: 0000-0001-6445-0631
authors: M
authors: Brock
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D054428:Chemokine CX3CL1 / Q000235:genetics* / Q000378:metabolism; D045424:Complex Mixtures / Q000633:toxicity; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic; D056464:Histone Deacetylase 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000737:chemistry / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D054428:Chemokine CX3CL1; D045424:Complex Mixtures; D056464:Histone Deacetylase 2; D007375:Interleukin-1; D008070:Lipopolysaccharides; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha; C515538:CX3CL1 protein, human; C525067:MIR223, human; C533423:HDAC2 protein, human
keywords: Chronic obstructive pulmonary disease; Histone deacetylase 2; Inflammation; microRNA