title: Peptidylarginine deiminase 4 promotes age-related organ fibrosis.
abstract: Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4-/-mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4-/-mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4-/-myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Kimberly
authors.identifier: 0000-0002-1026-6107
authors.initials: K
authors.lastname: Martinod
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Thilo
authors.identifier: 0000-0003-4003-1269
authors.initials: T
authors.lastname: Witsch
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Luise
authors.initials: L
authors.lastname: Erpenbeck
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Alexander
authors.initials: A
authors.lastname: Savchenko
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Deya
authors.initials: D
authors.lastname: Cherpokova
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Maureen
authors.initials: M
authors.lastname: Gallant
authors.affiliation: Faculty of Biology, University of Freiburg, 79106 Freiburg, Germany.|Department of Cardiology and Angiology I, Heart Center, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Mauler
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cifuni
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 denisa.wagner@childrens.harvard.edu.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Denisa D
authors.identifier: 0000-0002-4494-413X
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000367:Age Factors; D000818:Animals; D003094:Collagen / Q000378:metabolism; D065206:Extracellular Traps / Q000502:physiology; D005355:Fibrosis; D006867:Hydrolases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D000080002:Protein-Arginine Deiminase Type 4; D011658:Pulmonary Fibrosis / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D017382:Reactive Oxygen Species; D003094:Collagen; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse