title: Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice.
abstract: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function is unclear.
  
  
  
  To study the effect of CF ablation on cardiac remodeling.
  
  
  
  We characterized subgroups of murine CF by single-cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated bacterial artificial chromosome-transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single-cell transcriptional analysis revealed reduced CF activation but increased expression of prohypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy.
  
  
  
  Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Harmandeep
authors.initials: H
authors.lastname: Kaur
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: C Y
authors.initials: CY
authors.lastname: Ngai
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Jorge
authors.initials: J
authors.lastname: Carvalho
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Julia
authors.initials: J
authors.lastname: Bayer
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Astrid
authors.initials: A
authors.lastname: Wietelmann
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Ansgar
authors.initials: A
authors.lastname: Poetsch
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Soraya
authors.initials: S
authors.lastname: Hoelper
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Helge
authors.initials: H
authors.lastname: Möllmann
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Mario
authors.initials: M
authors.lastname: Looso
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Christian
authors.initials: C
authors.lastname: Troidl
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: From the Department of Pharmacology (H.K., C.Y.N., J.C., S.O., N.W.), Bioinformatics Facility (J.B., M.L.), Nuclear Magnetic Resonance Imaging Facility (A.W.), and Mass Spectrometry Group (A.P., S.H.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (M.T.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.); Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany (H.M., C.T.); and Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany (S.O., N.W.). nina.wettschureck@mpi-bn.mpg.de.
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
mesh_terms: D000809:Angiotensins / Q000633:toxicity; D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D000809:Angiotensins; D015815:Cell Adhesion Molecules; C082838:Postn protein, mouse
keywords: extracellular matrix; fibroblast; heart failure; myocardial infarction; phenotype